|
Inhibition of beta-lactamase at 100 uM
|
None
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
Inhibition of chymotrypsin at 250 uM
|
unidentified
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
Compound was evaluated for the inhibitory activity against human platelet aggregation by COL/ADP cartridges at a concentration of 1 x 10 e-3 M
|
Homo sapiens
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiplatelet activity of gemfibrozil chiral analogues.
Year : 2002
Volume : 12
Issue : 5
First Page : 817
Last Page : 821
Authors : Ammazzalorso A, Amoroso R, Baraldi M, Bettoni G, Braghiroli D, De Filippis B, Duranti A, Moretti M, Tortorella P, Tricca ML, Vezzalini F.
Abstract : The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency.
|
Compound was evaluated for the inhibitory activity against human platelet aggregation by COL/ADP cartridges at a concentration of 2 x 10 e-3 M
|
Homo sapiens
|
2.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiplatelet activity of gemfibrozil chiral analogues.
Year : 2002
Volume : 12
Issue : 5
First Page : 817
Last Page : 821
Authors : Ammazzalorso A, Amoroso R, Baraldi M, Bettoni G, Braghiroli D, De Filippis B, Duranti A, Moretti M, Tortorella P, Tricca ML, Vezzalini F.
Abstract : The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency.
|
Compound was evaluated for the inhibitory activity against human platelet aggregation by COL/ADP cartridges at a concentration of 3 x 10 e-3 M
|
Homo sapiens
|
17.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiplatelet activity of gemfibrozil chiral analogues.
Year : 2002
Volume : 12
Issue : 5
First Page : 817
Last Page : 821
Authors : Ammazzalorso A, Amoroso R, Baraldi M, Bettoni G, Braghiroli D, De Filippis B, Duranti A, Moretti M, Tortorella P, Tricca ML, Vezzalini F.
Abstract : The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency.
|
Compound was evaluated for the inhibitory activity against human platelet aggregation by COL/ADP cartridges at a concentration of 4 x 10 e-3 M
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiplatelet activity of gemfibrozil chiral analogues.
Year : 2002
Volume : 12
Issue : 5
First Page : 817
Last Page : 821
Authors : Ammazzalorso A, Amoroso R, Baraldi M, Bettoni G, Braghiroli D, De Filippis B, Duranti A, Moretti M, Tortorella P, Tricca ML, Vezzalini F.
Abstract : The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency.
|
Compound was evaluated for the inhibitory activity against human platelet aggregation by COL/ADP cartridges at a concentration of 5 x 10 e-3 M
|
Homo sapiens
|
100.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antiplatelet activity of gemfibrozil chiral analogues.
Year : 2002
Volume : 12
Issue : 5
First Page : 817
Last Page : 821
Authors : Ammazzalorso A, Amoroso R, Baraldi M, Bettoni G, Braghiroli D, De Filippis B, Duranti A, Moretti M, Tortorella P, Tricca ML, Vezzalini F.
Abstract : The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency.
|
Compound was tested for the inhibition of malate dehydrogenase (MDH) at 200 uM
|
None
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
In vitro inhibitory activity against rat microsomal lipid peroxidation (m-LPO)
|
Rattus norvegicus
|
0.1
ug.mL-1
|
|
Journal : J. Med. Chem.
Title : Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation.
Year : 1989
Volume : 32
Issue : 2
First Page : 421
Last Page : 428
Authors : Yoshioka T, Fujita T, Kanai T, Aizawa Y, Kurumada T, Hasegawa K, Horikoshi H.
Abstract : A series of hindered phenols were investigated as hypolipidemic and/or hypoglycemic agents with ability to inhibit lipid peroxidation. 1,3-Benzoxathioles (9 and 22), phenoxypentanoic acid (34), phenoxypentanol (35a), phenoxynonanol (35b), phenylchloropropionic acid having a chromanyl group (25), and a thiazolidine compound (27) derived from 25, all having a hindered phenol group, were prepared and examined. Compound 27 showed the expected biological properties in vivo and in vitro without any liver weight increase. Biological activities of the analogous thiazolidine compounds, 43-58, were compared. Thus, (+/-)-5-[4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]- benzyl]-2,4-thiazolidinedione (27) (CS-045) was found to have all of our expected properties and was selected as a candidate for further development as a hypoglycemic and hypolipidemic agent.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
59.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
14.4
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
15.1
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Antidyslipidemic activity in high fat diet fed Rattus norvegicus Charles Foster (rat) assessed as inhibition of cholesterol-induced phospholipid level in liver at 100 mg/kg, po administered QD for 30 days relative to control
|
Rattus norvegicus
|
-32.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in high fat diet fed Rattus norvegicus Charles Foster (rat) assessed as inhibition of cholesterol-induced triglyceride level in liver at 100 mg/kg, po administered QD for 30 days relative to control
|
Rattus norvegicus
|
-31.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in high fat diet fed Rattus norvegicus Charles Foster (rat) assessed as inhibition of cholesterol-induced total cholesterol level in liver at 100 mg/kg, po administered QD for 30 days relative to control
|
Rattus norvegicus
|
-28.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in high fat diet fed Rattus norvegicus Charles Foster (rat) assessed as inhibition of cholesterol-induced protein level in plasma at 100 mg/kg, po administered QD for 30 days relative to control
|
Rattus norvegicus
|
-31.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in high fat diet fed Rattus norvegicus Charles Foster (rat) assessed as inhibition of cholesterol-induced phospholipid level in plasma at 100 mg/kg, po administered QD for 30 days relative to control
|
Rattus norvegicus
|
-31.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in high fat diet fed Rattus norvegicus Charles Foster (rat) assessed as inhibition of cholesterol-induced triglyceride level in plasma at 100 mg/kg, po administered QD for 30 days relative to control
|
Rattus norvegicus
|
-34.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in high fat diet fed Rattus norvegicus Charles Foster (rat) assessed as inhibition of cholesterol-induced total cholesterol level in plasma at 100 mg/kg, po administered QD for 30 days relative to control
|
Rattus norvegicus
|
-34.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in Rattus norvegicus Charles Foster (rat) assessed as inhibition of triton WR1339-induced protein level in plasma at 100 mg/kg, po after 18 hr relative to control
|
Rattus norvegicus
|
-30.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in Rattus norvegicus Charles Foster (rat) assessed as inhibition of triton WR1339-induced phospholipid in plasma at 100 mg/kg, po after 18 hr relative to control
|
Rattus norvegicus
|
-34.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in Rattus norvegicus Charles Foster (rat) assessed as inhibition of triton WR1339-induced triglyceride in plasma at 100 mg/kg, po after 18 hr relative to control
|
Rattus norvegicus
|
36.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Antidyslipidemic activity in Rattus norvegicus Charles Foster (rat) assessed as inhibition of triton WR1339-induced total cholesterol in plasma at 100 mg/kg, po after 18 hr relative to control
|
Rattus norvegicus
|
-36.0
%
|
|
Journal : Med Chem Res
Title : Expedient synthesis of some novel pregnane derivatives and their evaluation as anti-oxidant and anti-dyslipidemic agents
Year : 2011
Volume : 20
Issue : 1
First Page : 36
Last Page : 46
Authors : Sethi A, Bhatia G, Khanna AK, Khan MM, Bishnoi A, Pandey AK, Maurya A
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
56.21
%
|
|
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
|
71.16
%
|
|
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.
|
Binding affinity to TTR (unknown origin) by isothermal titration calorimetric analysis
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Enthalpic Forces Correlate with the Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma.
Year : 2015
Volume : 58
Issue : 16
First Page : 6507
Last Page : 6515
Authors : Iakovleva I, Brännström K, Nilsson L, Gharibyan AL, Begum A, Anan I, Walfridsson M, Sauer-Eriksson AE, Olofsson A.
Abstract : The plasma protein transthyretin (TTR) is linked to human amyloidosis. Dissociation of its native tetrameric assembly is a rate-limiting step in the conversion from a native structure into a pathological amyloidogenic fold. Binding of small molecule ligands within the thyroxine binding site of TTR can stabilize the tetrameric integrity and is a potential therapeutic approach. However, through the characterization of nine different tetramer-stabilizing ligands we found that unspecific binding to plasma components might significantly compromise ligand efficacy. Surprisingly the binding strength between a particular ligand and TTR does not correlate well with its selectivity in plasma. However, through analysis of the thermodynamic signature using isothermal titration calorimetry we discovered a better correlation between selectivity and the enthalpic component of the interaction. This is of specific interest in the quest for more efficient TTR stabilizers, but a high selectivity is an almost universally desired feature within drug design and the finding might have wide-ranging implications for drug design.
|
Inhibition of human recombinant COX1 expressed in Sf9 cell microsomes assessed as reduction in conversion of arachidonic acid to PGE2 at 250 uM incubated for 5 mins by HTRF assay
|
Homo sapiens
|
18.0
%
|
|
Journal : J. Med. Chem.
Title : Impact of Binding Site Comparisons on Medicinal Chemistry and Rational Molecular Design.
Year : 2016
Volume : 59
Issue : 9
First Page : 4121
Last Page : 4151
Authors : Ehrt C, Brinkjost T, Koch O.
Abstract : Modern rational drug design not only deals with the search for ligands binding to interesting and promising validated targets but also aims to identify the function and ligands of yet uncharacterized proteins having impact on different diseases. Additionally, it contributes to the design of inhibitors with distinct selectivity patterns and the prediction of possible off-target effects. The identification of similarities between binding sites of various proteins is a useful approach to cope with those challenges. The main scope of this perspective is to describe applications of different protein binding site comparison approaches to outline their applicability and impact on molecular design. The article deals with various substantial application domains and provides some outstanding examples to show how various binding site comparison methods can be applied to promote in silico drug design workflows. In addition, we will also briefly introduce the fundamental principles of different protein binding site comparison methods.
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In vivo inhibition of CYP2C8 in human assessed as reduction in gemfibrozil-1-O-glucuronide metabolite formation in plasma at 30 mg/kg, po administered as single dose measured after 10 hrs by LC-MS/MS analysis
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Glucuronides as Potential Anionic Substrates of Human Cytochrome P450 2C8 (CYP2C8).
Year : 2017
Volume : 60
Issue : 21
First Page : 8691
Last Page : 8705
Authors : Ma Y, Fu Y, Khojasteh SC, Dalvie D, Zhang D.
Abstract : Glucuronidation is in general considered as a terminal metabolic step that leads to direct elimination of drugs and generally abolishes their biological activity. However, there is growing evidence to suggest that glucuronides can be ligands of human CYP2C8, making CYP2C8 distinct from the other CYP isoforms. Several classes of glucuronide conjugates, which include acyl glucuronides, ether glucuronides, N-glucuronides, and carbamoyl glucuronides, have been shown to be substrates or time-dependent inhibitors of CYP2C8. Although the structures of CYP2C8-glucuronide complexes have not been determined, the structural features of CYP2C8 active site support its binding to anionic and bulky ligands like glucuronides. As interaction perpetrators with CYP2C8, glucuronides of gemfibrozil and clopidogrel showed marked clinical drug-drug interactions (e.g., with cerivastatin and repaglinide), which are more than expected from the parent drug. This review summarizes glucuronides as CYP2C8 ligands and the active-site structural features of CYP2C8 that allow potential binding to glucuronides.
|
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
|
11.1
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
2.56
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
7.25
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
4.27
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
19.84
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
8.15
%
|
|
|
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
|
-1.55
%
|
|
|
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
|
3.12
%
|
|
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
|
7.55
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
31.76
%
|
|
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
|
0.38
%
|
|
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
|
-0.17
%
|
|
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
|
0.38
%
|
|
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
|
-0.17
%
|
|
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.
