ArticleDrug metabolism and disposition: the biological fate of chemicals2010
Quantifying and predicting the promiscuity and isoform specificity of small-molecule cytochrome P450 inhibitors.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Thermostable ancestors enabled evolutionary diversification of promiscuous chemical defence enzymes.The EMBO journal · 2026Article
- Designing cytochrome P450 enzymes for use in cancer gene therapy.Frontiers in bioengineering and biotechnology · 2024Review
- Promiscuous Ribozymes and Their Proposed Role in Prebiotic Evolution.Chemical reviews · 2020Review
- The Rational Discovery of a Tau Aggregation Inhibitor.Biochemistry · 2018Article
- Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases.Journal of enzyme inhibition and medicinal chemistry · 2016Article
- Biological messiness vs. biological genius: Mechanistic aspects and roles of protein promiscuity.The Journal of steroid biochemistry and molecular biology · 2015Review
- Structure-Based Small Molecule Modulation of a Pre-Amyloid State: Pharmacological Enhancement of IAPP Membrane-Binding and Toxicity.Biochemistry · 2015Article
- Efficient searching and annotation of metabolic networks using chemical similarity.Bioinformatics (Oxford, England) · 2015Article
- Molecular annotation of ketol-acid reductoisomerases from Streptomyces reveals a novel amino acid biosynthesis interlock mediated by enzyme promiscuity.Microbial biotechnology · 2015Article
- Cleavage entropy as quantitative measure of protease specificity.PLoS computational biology · 2013Article
- Catalytic versus inhibitory promiscuity in cytochrome P450s: implications for evolution of new function.Biochemistry · 2011Article
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Authors and funding
5 authors.
Funding
Abstract
Drug promiscuity (i.e., inhibition of multiple enzymes by a single compound) is increasingly recognized as an important pharmacological consideration in the drug development process. However, systematic studies of functional or physicochemical characteristics that correlate with drug promiscuity are handicapped by the lack of a good way of quantifying promiscuity. In this article, we present a new entropy-based index of drug promiscuity. We apply this index to two high-throughput data sets describing inhibition of cytochrome P450 isoforms by small-molecule drugs and drug candidates, and we demonstrate how drug promiscuity or specificity can be quantified. For these drug-metabolizing enzymes, we find that there is essentially no correlation between a drug's potency and specificity. We also present an index to quantify the susceptibilities of different enzymes to inhibition by diverse substrates. Finally, we use partial least-squares regression to successfully predict isoform specificity and promiscuity of small molecules, using a set of fingerprint-based descriptors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.