An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.

ABSTRACT: Identification of structural determinants required for potent inhibition of drug-metabolizing cytochrome P450 3A4 (CYP3A4) could help develop safer drugs and more effective pharmacoenhancers. We utilize a rational inhibitor design to decipher structure-activity relationships in analogues of ritonavir, a highly potent CYP3A4 inhibitor marketed as pharmacoenhancer. Analysis of compounds with the R₁ side-group as phenyl or naphthalene and R₂ as indole or naphthalene in different stereo configuration showed that (i) analogues with the R₂-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R₂-phenyl/indole containing counterparts; (ii) stereochemistry becomes a more important contributing factor, as the bulky side-groups limit t

SUBMITTER: Samuels ER 

PROVIDER: S-EPMC7179874 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature