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Publication Abstract from PubMed

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 muM vs. 0.130 muM, respectively).

An increase in side-group hydrophobicity largely improves the potency of ritonavir-like inhibitors of CYP3A4.,Samuels ER, Sevrioukova IF Bioorg Med Chem. 2020 Mar 15;28(6):115349. doi: 10.1016/j.bmc.2020.115349. Epub, 2020 Jan 31. PMID:32044230^[2]

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