Trainable structure–activity relationship model for virtual screening of CYP3A4 inhibition

Didžiapetris, Remigijus; Dapkūnas, Justas; Sazonovas, Andrius; Japertas, Pranas

doi:10.1007/s10822-010-9381-1

Cited by 32 publications

(30 citation statements)

References 39 publications

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“…Owing to recent structural and computer modeling advances, QSAR methodology was utilized in combination with the multiple pharmacophore hypothesis approach [112], advanced docking techniques (MetSite, GLUE, AutoDock and other) [113–116], GALAS (Global Adjusted Locally According to Similarity) method [117, 118], structure-based comparative molecular field analysis [119], and NMR spectroscopy data [120]. Gaussian kernel weighted k -nearest neighbor models were also used for in silico prediction of CYP3A4 inhibitors [121].…”

Section: 3 Computational Approachesmentioning

confidence: 99%

Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

Sevrioukova

Poulos

2015

Advances in Experimental Medicine and Biology

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Cytochrome P450 3A4 (CYP3A4) is the major and most important drug-metabolizing enzyme in humans that oxidizes and clears over a half of all administered pharmaceuticals. This is possible because CYP3A4 is promiscuous with respect to substrate binding and has the ability to catalyze diverse oxidative chemistries in addition to traditional hydroxylation reactions. Furthermore, CYP3A4 binds and oxidizes a number of substrates in a cooperative manner and can be both induced and inactivated by drugs. In vivo, CYP3A4 inhibition could lead to undesired drug-drug interactions and drug toxicity, a major reason for late-stage clinical failures and withdrawal of marketed pharmaceuticals. Owing to its central role in drug metabolism, many aspects of CYP3A4 catalysis have been extensively studied by various techniques. Here, we give an overview of experimental and theoretical methods currently used for investigation and prediction of CYP3A4-ligand interactions, a defining factor in drug metabolism, with an emphasis on the problems addressed and conclusions derived from the studies.

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Section: 3 Computational Approachesmentioning

confidence: 99%

Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

Sevrioukova

Poulos

2015

Advances in Experimental Medicine and Biology

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“…For example, QSAR studies by Lewis et al (2006) showed that a linear relationship existed between lipophilicity and potency for 15 inhibitors/substrates of CYP2C9, including nonsteroidal anti-inflammatory drugs. Modeling by Didziapetris et al (2010) demonstrated that an increase in the size of the molecule with the incorporation of hydrophobic aliphatic or aromatic residues resulted in a higher probability for the compound to inhibit CYP3A4. Roy and Pratim Roy (2009) also demonstrated that logP appeared to be the most important factor affecting the inhibition potency of CYP3A4 inhibitors.…”

Section: Consideration Of Clinically Relevant Levels and Inhibition Pmentioning

confidence: 99%

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Tweedie

2012

Drug Metab Dispos

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The 2012 drug-drug interaction (DDI) guidance from the European Medicines Agency (EMA) and the draft DDI guidance from the Food and Drug Administration (FDA) have proposed that metabolites present at >25% of the parent area under the time-concentration curve (AUC) (EMA and FDA) and >10% of the total drug-related exposure (EMA) should be investigated in vitro for their DDI potential. This commentary attempts to rationalize the clinically relevant levels of metabolite(s) that contribute to DDI by considering not only the abundance but also inhibition potency, physicochemical properties, and structural alerts of the metabolite. A decision tree is proposed for levels of metabolites that could trigger in vitro DDI assessment. When the parent is an inhibitor of cytochrome P450s (P450s), clinical DDI studies will assess the in vivo DDI effect of the combination of parent and metabolite(s).When the parent is not a P450 inhibitor, it is important to assess the inhibition potential of abundant metabolites in vitro. The proposal is to apply a default cutoff value of metabolite level which is 100% of the parent AUC. It is important to note that exceptions can occur, and different metabolite levels may be considered depending on the physiochemical properties of metabolites (e.g., increased lipophilicity) and whether the metabolite contains structural alerts for DDI (e.g., mechanism-based inhibition). A key objective of this commentary is to stimulate discussions among the scientific community on this important topic, so that appropriate in vitro metabolism studies are conducted on metabolites, to ensure the safety of drugs in development balanced with the desire to avoid creating unnecessary studies that will add little to no value in ensuring patient safety.

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“…All points considered, metabolites are, in general, unlikely to be more potent P450 inhibitors than their respective parent drugs. Several published quantitative structure-activity relationship models evaluating reversible inhibition of CYP2C and CYP3A families also supported the positive correlation between lipophilicity (logP) and potency for enzyme inhibition (Lewis et al, 2006;Didziapetris et al, 2010). In addition, empirical observations indicate that metabolites are likely to have affinity for the same binding sites as the parent (e.g., binding to the pharmacological target of the parent leading to "active metabolites") and if a metabolite has any affinity for P450 binding sites, the binding pattern tends to be very similar to the parent (Humphreys and Unger, 2006).…”

Section: Risk Assessment Of Contribution Of Metabolites To P450mentioning

confidence: 72%

Contribution of Metabolites to P450 Inhibition–Based Drug–Drug Interactions: Scholarship from the Drug Metabolism Leadership Group of the Innovation and Quality Consortium Metabolite Group

Balani

Chen

et al. 2015

Drug Metab Dispos

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Recent European Medicines Agency (final) and US Food and Drug Administration (draft) drug interaction guidances proposed that human circulating metabolites should be investigated in vitro for their drug-drug interaction (DDI) potential if present at ‡25% of the parent area under the time-concentration curve (AUC) (US Food and Drug Administration) or ‡25% of the parent and ‡10% of the total drug-related AUC (European Medicines Agency). To examine the application of these regulatory recommendations, a group of scientists, representing 18 pharmaceutical companies of the Drug Metabolism Leadership Group of the Innovation and Quality Consortium, conducted a scholarship to assess the risk of contributions by metabolites to cytochrome P450 (P450) inhibition-based DDIs. The group assessed the risk of having a metabolite as the sole contributor to DDI based on literature data and analysis of the 137 most frequently prescribed drugs, defined structural alerts associated with P450 inhibition/inactivation by metabolites, and analyzed current approaches to trigger in vitro DDI studies for metabolites. The group concluded that the risk of P450 inhibition caused by a metabolite alone is low. Only metabolites from 5 of 137 drugs were likely the sole contributor to the in vivo P450 inhibition-based DDIs. Two recommendations were provided when assessing the need to conduct in vitro P450 inhibition studies for metabolites: 1) consider structural alerts that suggest P450 inhibition potential, and 2) use multiple approaches (e.g., a metabolite cut-off value of 100% of the parent AUC and the R met strategy) to predict P450 inhibition-based DDIs caused by metabolites in the clinic.

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Trainable structure–activity relationship model for virtual screening of CYP3A4 inhibition

Cited by 32 publications

References 39 publications

Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

Current Approaches for Investigating and Predicting Cytochrome P450 3A4-Ligand Interactions

A Perspective on the Contribution of Metabolites to Drug-Drug Interaction Potential: The Need to Consider Both Circulating Levels and Inhibition Potency

Contribution of Metabolites to P450 Inhibition–Based Drug–Drug Interactions: Scholarship from the Drug Metabolism Leadership Group of the Innovation and Quality Consortium Metabolite Group

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