Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities.

ABSTRACT: Structure-function relationships of nine rationally designed ritonavir-like compounds were investigated to better understand the ligand binding and inhibitory mechanism in human drug-metabolizing cytochrome P450 3A4 (CYP3A4). The analogs had a similar backbone and pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating and terminal groups, respectively. N-Isopropyl, N-cyclopentyl, or N-phenyl were the R₁-side group substituents alone (compounds 5a-c) or in combination with phenyl or indole at the R₂ position (8a-c and 8d-f subseries, respectively). Our experimental and structural data indicate that (i) for all analogs, a decrease in the dissociation constant (K_s) coincides with a decrease in IC₅₀, but no relation with other derived paramete

SUBMITTER: Samuels ER 

PROVIDER: S-EPMC5859942 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature