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Publication Abstract from PubMed

Human cytochrome P450 3A4 (CYP3A4) is a key xenobiotic-metabolizing enzyme that oxidizes and clears the majority of drugs. CYP3A4 inhibition may lead to drug-drug interactions, toxicity and other adverse effects but, in some cases, could be beneficial and enhance therapeutic efficiency of co-administered pharmaceuticals that are metabolized by CYP3A4. Based on our investigations of analogs of ritonavir, a potent CYP3A4 inactivator and pharmacoenhancer, we have built a pharmacophore model for a CYP3A4-specific inhibitor. This study is the first attempt to test this model using a set of rationally designed compounds. The functional and structural data presented here agree well with the proposed pharmacophore. In particular, we confirmed the importance of a flexible backbone, the H-bond donor/acceptor moiety and aromaticity of the side group analogous to Phe-2 of ritonavir, and demonstrated the leading role of hydrophobic interactions at the sites adjacent to the heme and phenylalanine cluster in the ligand binding process. The X-ray structures of CYP3A4 bound to the rationally designed inhibitors provide deeper insights into the mechanism of the CYP3A4-ligand interaction. Most importantly, two of our compounds (15a and 15b) that are less complex than ritonavir have comparable sub-micromolar affinity and inhibitory potency for CYP3A4 and, thus, could serve as templates for synthesis of second generation inhibitors for further evaluation and optimization of the pharmacophore model.

Structure-based inhibitor design for evaluation of a CYP3A4 pharmacophore model.,Kaur P, Chamberlin R, Poulos TL, Sevrioukova IF J Med Chem. 2015 Sep 29. PMID:26371436^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.