6daa

Publication Abstract from PubMed

In a continuing effort to identify structural attributes required for strong binding and potent inhibition of human drug-metabolizing CYP3A4, we designed ten ritonavir-like analogs differing in the side-group stereochemistry, backbone atomic composition, and head-group spacing. All analogs had pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating and tail groups, respectively, phenyl side-groups, and either a methyl- or ethyl-pyridyl linker. Each linker subseries had S/R, R/S, R/R and S/S side-group conformers (4a-d and 4e-h, respectively), and one S/S stereoisomer with the backbone S-to-N-heteroatom substitution (6a and 6b). To elucidate structure-activity relationships, ligand-dependent changes in optical spectra, dissociation constant (Ks), inhibitory potency (IC50), thermostability, and heme ligation and reduction kinetics were analyzed. Comparison of the subseries and individual compounds showed that CYP3A4 only weakly discriminates between side-group configurations, associates more tightly with the pyridyl-ethyl-linker analogs, and strongly disfavors the N-containing backbone. Ks and IC50 for the pyridyl-ethyl R/R conformer, 4g, were the lowest and close to those for ritonavir: 0.04 and 0.31 microM versus 0.02 and 0.13 microM, respectively. Determination of the X-ray structures of the inhibitory complexes was critical for experimental data interpretation, especially for the uniquely oriented 4a and 4e. Based on structural analysis we conclude that, for this series of analogs, the ligand-mediated interactions near the heme are dominant and define the binding mode, and that fine-tuning of these interactions, as well as the backbone spacing could further improve the affinity and inhibitory strength.

Structure-activity relationships of rationally designed ritonavir analogs: Impact of side-group stereochemistry, head-group spacing, and backbone composition on the interaction with CYP3A4.,Samuels ER, Sevrioukova I Biochemistry. 2019 Mar 26. doi: 10.1021/acs.biochem.9b00156. PMID:30912932^[2]

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