|
Inhibition of human recombinant full length CA4 by stopped-flow CO2 hydration method
|
Homo sapiens
|
213.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
Year : 2009
Volume : 17
Issue : 3
First Page : 1214
Last Page : 1221
Authors : Temperini C, Cecchi A, Scozzafava A, Supuran CT.
Abstract : Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.
|
Inhibition of human recombinant full length CA5A by stopped-flow CO2 hydration method
|
Homo sapiens
|
890.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
Year : 2009
Volume : 17
Issue : 3
First Page : 1214
Last Page : 1221
Authors : Temperini C, Cecchi A, Scozzafava A, Supuran CT.
Abstract : Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.
|
Inhibition of human recombinant full length CA5B by stopped-flow CO2 hydration method
|
Homo sapiens
|
274.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
Year : 2009
Volume : 17
Issue : 3
First Page : 1214
Last Page : 1221
Authors : Temperini C, Cecchi A, Scozzafava A, Supuran CT.
Abstract : Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.
|
Inhibition of human recombinant full length CA7 by stopped-flow CO2 hydration method
|
Homo sapiens
|
0.23
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
Year : 2009
Volume : 17
Issue : 3
First Page : 1214
Last Page : 1221
Authors : Temperini C, Cecchi A, Scozzafava A, Supuran CT.
Abstract : Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.
|
Inhibition of human recombinant CA9 catalytic domain by stopped-flow CO2 hydration method
|
Homo sapiens
|
36.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
Year : 2009
Volume : 17
Issue : 3
First Page : 1214
Last Page : 1221
Authors : Temperini C, Cecchi A, Scozzafava A, Supuran CT.
Abstract : Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.
|
Inhibition of human recombinant CA12 catalytic domain by stopped-flow CO2 hydration method
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
Year : 2009
Volume : 17
Issue : 3
First Page : 1214
Last Page : 1221
Authors : Temperini C, Cecchi A, Scozzafava A, Supuran CT.
Abstract : Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.
|
Inhibition of mouse recombinant full length CA13 by stopped-flow CO2 hydration method
|
Mus musculus
|
13.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.
Year : 2009
Volume : 17
Issue : 3
First Page : 1214
Last Page : 1221
Authors : Temperini C, Cecchi A, Scozzafava A, Supuran CT.
Abstract : Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.
|
Binding affinity to human recombinant carbonic anhydrase 2 by thermal shift assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII.
Year : 2010
Volume : 18
Issue : 21
First Page : 7357
Last Page : 7364
Authors : Čapkauskaitė E, Baranauskienė L, Golovenko D, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2-benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed.
|
Binding affinity to human recombinant carbonic anhydrase 7 by thermal shift assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII.
Year : 2010
Volume : 18
Issue : 21
First Page : 7357
Last Page : 7364
Authors : Čapkauskaitė E, Baranauskienė L, Golovenko D, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2-benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed.
|
Binding affinity to human recombinant carbonic anhydrase 13 by thermal shift assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII.
Year : 2010
Volume : 18
Issue : 21
First Page : 7357
Last Page : 7364
Authors : Čapkauskaitė E, Baranauskienė L, Golovenko D, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2-benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed.
|
Binding affinity to human recombinant carbonic anhydrase 2 by isothermal titration calorimetry assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII.
Year : 2010
Volume : 18
Issue : 21
First Page : 7357
Last Page : 7364
Authors : Čapkauskaitė E, Baranauskienė L, Golovenko D, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2-benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed.
|
Binding affinity to human recombinant carbonic anhydrase 13 by isothermal titration calorimetry assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII.
Year : 2010
Volume : 18
Issue : 21
First Page : 7357
Last Page : 7364
Authors : Čapkauskaitė E, Baranauskienė L, Golovenko D, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2-benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed.
|
Binding affinity to human recombinant carbonic anhydrase 13 by thermal shift assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII.
Year : 2013
Volume : 21
Issue : 22
First Page : 6937
Last Page : 6947
Authors : Čapkauskaitė E, Zubrienė A, Smirnov A, Torresan J, Kišonaitė M, Kazokaitė J, Gylytė J, Michailovienė V, Jogaitė V, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5 nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.(1) Systematic structure-activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms.
|
Binding affinity to human recombinant carbonic anhydrase 7 by thermal shift assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII.
Year : 2013
Volume : 21
Issue : 22
First Page : 6937
Last Page : 6947
Authors : Čapkauskaitė E, Zubrienė A, Smirnov A, Torresan J, Kišonaitė M, Kazokaitė J, Gylytė J, Michailovienė V, Jogaitė V, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5 nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.(1) Systematic structure-activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms.
|
Binding affinity to human recombinant carbonic anhydrase 6 expressed in Escherichia coli Rosetta2 (DE3) by thermal shift assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII.
Year : 2013
Volume : 21
Issue : 22
First Page : 6937
Last Page : 6947
Authors : Čapkauskaitė E, Zubrienė A, Smirnov A, Torresan J, Kišonaitė M, Kazokaitė J, Gylytė J, Michailovienė V, Jogaitė V, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5 nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.(1) Systematic structure-activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms.
|
Binding affinity to human recombinant carbonic anhydrase 2 by thermal shift assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII.
Year : 2013
Volume : 21
Issue : 22
First Page : 6937
Last Page : 6947
Authors : Čapkauskaitė E, Zubrienė A, Smirnov A, Torresan J, Kišonaitė M, Kazokaitė J, Gylytė J, Michailovienė V, Jogaitė V, Manakova E, Gražulis S, Tumkevičius S, Matulis D.
Abstract : Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5 nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.(1) Systematic structure-activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
80.06
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
97.5
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of human recombinant carbonic anhydrase 7 preincubated for 15 mins by stopped flow CO2 hydration assay
|
Homo sapiens
|
0.23
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Structure-based screening for the discovery of new carbonic anhydrase VII inhibitors.
Year : 2014
Volume : 71
First Page : 105
Last Page : 111
Authors : De Luca L, Ferro S, Damiano FM, Supuran CT, Vullo D, Chimirri A, Gitto R.
Abstract : Among the different mammalian isoforms of Carbonic Anhydrase, the hCA VII is mainly expressed in the brain where it is involved in several neurological diseases. Thereby hCA VII has been validated as an attractive target for the discovery of selective inhibitors for the treatment of epilepsy and neurological pain. To identify new chemical entities as carbonic anhydrase inhibitors (CAIs) targeting hCA VII, we used a structure-based approach. By means of LigandScout software we built pharmacophore models from crystal structures of two well-known CAIs in complex with hCA VII. A merged pharmacophore hypothesis has been obtained. Subsequently, a focused library of compounds was screened against pharmacophore model and the most interesting hits were docked into the crystal structure of hCA VII. As a result, we identified new compounds displaying significant CA inhibitory effects in the nanomolar range.
|
Binding affinity to recombinant human full length N-terminal His-tagged carbonic anhydrase 2 (1 to 260 residues) expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
530.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 4 expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
77.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human full length N-terminal His6-tagged mitochondrial carbonic anhydrase 5A expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
670.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human full length N-terminal His6-tagged mitochondrial carbonic anhydrase 5B (40 to 317 residues) expressed in Escherichia coli Rosetta 2 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
59.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 6 expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
710.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His-tagged carbonic anhydrase 7 (3 to 264 residues) expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human carbonic anhydrase 9 (1 to 260 residues) expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
430.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human full length N-terminal His-tagged carbonic anhydrase 13 (1 to 262 residues) expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 14 (20 to 280 residues) expressed in Escherichia coli BL21 (DE3) in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
63.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 1 (3 to 261 residues) expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
261.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human full length N-terminal His-tagged carbonic anhydrase 2 (1 to 260 residues) expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
3.77
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 3 (4 to 260 residues) expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
105.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 4 expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
0.33
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human full length N-terminal His6-tagged mitochondrial carbonic anhydrase 5A expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
6.96
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human full length N-terminal His6-tagged mitochondrial carbonic anhydrase 5B (40 to 317 residues) expressed in Escherichia coli Rosetta 2 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
0.46
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 6 expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
1.01
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His-tagged carbonic anhydrase 7 (3 to 264 residues) expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
1.46
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human carbonic anhydrase 9 (1 to 260 residues) expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
2.03
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human carbonic anhydrase 12 (1 to 260 residues) expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
12.2
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human full length N-terminal His-tagged carbonic anhydrase 13 (1 to 262 residues) expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
4.11
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Binding affinity to recombinant human N-terminal His6-tagged carbonic anhydrase 14 (20 to 280 residues) expressed in Escherichia coli BL21 (DE3) assessed as intrinsic dissociation constant in presence of ANS by fluorescent thermal shift assay
|
Homo sapiens
|
0.38
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole design, synthesis, and docking to build selective carbonic anhydrase VA inhibitors.
Year : 2018
Volume : 26
Issue : 3
First Page : 675
Last Page : 687
Authors : Čapkauskaitė E, Zakšauskas A, Ruibys V, Linkuvienė V, Paketurytė V, Gedgaudas M, Kairys V, Matulis D.
Abstract : The similarity of human carbonic anhydrase (CA) active sites makes it difficult to design selective inhibitors for one or several CA isoforms that are drug targets. Here we synthesize a series of compounds that are based on 5-[2-(benzimidazol-1-yl)acetyl]-2-chloro-benzenesulfonamide (1a) which demonstrated picomolar binding affinity and significant selectivity for CA isoform five A (VA), and explain the structural influence of inhibitor functional groups to the binding affinity and selectivity. A series of chloro-substituted benzenesulfonamides bearing a heterocyclic tail, together with molecular docking, was used to build inhibitors that explore substituent influence on the binding affinity to the CA VA isoform.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
5.44
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-0.79
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
9.63
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
6.26
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
0.29
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
-0.23
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-0.18
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-5.29
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
0.586
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.11
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.11
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
