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

Authors: Samuels, Eric R; Sevrioukova, Irina F

Published In Bioorg Med Chem, (2020 03 15)

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 the ability to optimize protein-ligand interactions; (iii) the relationship between the R1/R2 configuration and preferential binding to CYP3A4 is complex and depends on the side-group functionality/interplay and backbone spacing; and (iv) three inhibitors, 5a-b and 7d, were superior to ritonavir (IC50 of 0.055-0.085 μM vs. 0.130 μM, respectively).

PubMed ID: 32044230

MeSH Terms: Cytochrome P-450 CYP3A Inhibitors/chemical synthesis; Cytochrome P-450 CYP3A Inhibitors/chemistry; Cytochrome P-450 CYP3A Inhibitors/pharmacology*; Cytochrome P-450 CYP3A/metabolism*; Dose-Response Relationship, Drug; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Structure; Ritonavir/chemical synthesis; Ritonavir/chemistry; Ritonavir/pharmacology*; Structure-Activity Relationship