{"title":"Evaluation of Larger Side-Group Functionalities and the Side/End-Group Interplay in Ritonavir-Like Inhibitors of CYP3A4.","authors":"Eric R Samuels, Irina F Sevrioukova","doi":"10.1111/cbdd.70043","DOIUrl":null,"url":null,"abstract":"<p><p>A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R<sub>2</sub> side-group and R<sub>3</sub> end-group interplay when the R<sub>1</sub> side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R<sub>1</sub>/R<sub>2</sub>-phenyl inhibitors upon elongation and/or fluorination of R<sub>3</sub>-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R<sub>3</sub> is pyridine, the impact of R<sub>2</sub>-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration. Overall, the R<sub>2</sub>-naphthalene/R<sub>3</sub>-pyridine containing 2f (R/S) was the series lead compound and one of the strongest binders/inhibitors designed thus far (K<sub>s</sub> = 0.009 μM; IC<sub>50</sub> = 0.10 μM). Introduction of a larger biphenyl or fluorene as R<sub>2</sub> did not lead to any improvements. Contrarily, fluorene-containing 13 was the series weakest binder and inhibitor (K<sub>s</sub> = 0.734 μM; IC<sub>50</sub> = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R<sub>2</sub>-biphenyl, however, can switch positions with R<sub>3</sub>-Boc to enable heme ligation. Thus, for small and chemically simple end-groups such as Boc and pyridine, the R<sub>2</sub>/R<sub>3</sub> interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.</p>","PeriodicalId":93931,"journal":{"name":"Chemical biology & drug design","volume":"105 1","pages":"e70043"},"PeriodicalIF":0.0000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11749023/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical biology & drug design","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1111/cbdd.70043","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R2 side-group and R3 end-group interplay when the R1 side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R1/R2-phenyl inhibitors upon elongation and/or fluorination of R3-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R3 is pyridine, the impact of R2-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration. Overall, the R2-naphthalene/R3-pyridine containing 2f (R/S) was the series lead compound and one of the strongest binders/inhibitors designed thus far (Ks = 0.009 μM; IC50 = 0.10 μM). Introduction of a larger biphenyl or fluorene as R2 did not lead to any improvements. Contrarily, fluorene-containing 13 was the series weakest binder and inhibitor (Ks = 0.734 μM; IC50 = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R2-biphenyl, however, can switch positions with R3-Boc to enable heme ligation. Thus, for small and chemically simple end-groups such as Boc and pyridine, the R2/R3 interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.