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Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism.

ABSTRACT: Cytochrome P450 enzymes function to catalyze a wide range of reactions, many of which are critically important for drug response. Members of the human cytochrome P450 3A (CYP3A) family are particularly important in drug clearance, and they collectively metabolize more than half of all currently prescribed medications. The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways. Emerging evidence suggests that individual enzymes in the CYP3A family play discrete and important roles in catalysis and disease progression. Here we review the similarities and differences among CYP3A enzymes with regard to substrate recognition, metabolism, modulation by small molecules, and biological consequence, highlighting some of those with clinical significance. We also present structural perspectives to further characterize the basis of these comparisons.

SUBMITTER: Wright WC

PROVIDER: S-EPMC7418881 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism.

Wright William C WC Chenge Jude J Chen Taosheng T

Liver research 20190829 3-4

Cytochrome P450 enzymes function to catalyze a wide range of reactions, many of which are critically important for drug response. Members of the human cytochrome P450 3A (CYP3A) family are particularly important in drug clearance, and they collectively metabolize more than half of all currently prescribed medications. The ability of these enzymes to bind a large and structurally diverse set of compounds increases the chances of their modulating or facilitating drug metabolism in unfavorable ways ...[more]

PMID: 32789028

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Project description:The eight mammalian Src-family tyrosine kinases are dynamic, multi-domain structures, which adopt distinct "open" and "closed" conformations. In the closed conformation, the regulatory SH3 and SH2 domains pack against the back of the kinase domain, providing allosteric control of kinase activity. Small molecule ligands that engage the regulatory SH3-SH2 region have the potential to modulate Src-family kinase activity for therapeutic advantage. Here we describe an HTS-compatible fluorescence polarization assay to identify small molecules that interact with the unique-SH3-SH2-linker (U32L) region of Hck, a Src-family member expressed exclusively in cells of myeloid lineage. Hck has significant potential as a drug target in acute myeloid leukemia, an aggressive form of cancer with substantial unmet clinical need. The assay combines recombinant Hck U32L protein with a fluorescent probe peptide that binds to the SH3 domain in U32L, resulting in an increased FP signal. Library compounds that interact with the U32L protein and interfere with probe binding reduce the FP signal, scoring as hits. Automated 384-well high-throughput screening of 60,000 compounds yielded Z'-factor coefficients > 0.7 across nearly 200 assay plates, and identified a series of hit compounds with a shared pyrimidine diamine substructure. Surface plasmon resonance assays confirmed direct binding of hit compounds to the Hck U32L target protein as well as near-full-length Hck. Binding was not observed with the individual SH3 and SH2 domains, demonstrating that these compounds recognize a specific three-dimensional conformation of the regulatory regions. This conclusion is supported by computational docking studies, which predict ligand contacts with a pocket formed by the juxtaposition of the SH3 domain, the SH3-SH2 domain connector, and the SH2-kinase linker. Each of the four validated hits stimulated recombinant, near-full-length Hck activity in vitro, providing evidence for allosteric effects on the kinase domain. These results provide a path to discovery and development of chemical scaffolds to target the regulatory regions of Hck and other Src family kinases as a new approach to pharmacological kinase control.

Dataset Information

Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism.

Publications

Structural Perspectives of the CYP3A Family and Their Small Molecule Modulators in Drug Metabolism.

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