{"doi":"10.1111/cbdd.70043","title":"Evaluation of Larger Side‐Group Functionalities and the Side/End‐Group Interplay in Ritonavir‐Like Inhibitors of <scp>CYP3A4</scp>","abstract":"ABSTRACT A new series of 13 ritonavir‐like inhibitors of human drug‐metabolizing CYP3A4 was rationally designed to study the R 2 side‐group and R 3 end‐group interplay when the R 1 side‐group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R 1 /R 2 ‐phenyl inhibitors upon elongation and/or fluorination of R 3 ‐Boc (tert‐butyloxycarbonyl) or its replacement with benzenesulfonyl. When R 3 is pyridine, the impact of R 2 ‐phenyl‐to‐indole/naphthalene substitution was multidirectional and highly dependent on side‐group stereo configuration. Overall, the R 2 ‐naphthalene/R 3 ‐pyridine containing 2f ( R / S ) was the series lead compound and one of the strongest binders/inhibitors designed thus far ( K s = 0.009 μM; IC 50 = 0.10 μM). Introduction of a larger biphenyl or fluorene as R 2 did not lead to any improvements. Contrarily, fluorene‐containing 13 was the series weakest binder and inhibitor ( K s = 0.734 μM; IC 50 = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R 2 ‐biphenyl, however, can switch positions with R 3 ‐Boc to enable heme ligation. Thus, for small and chemically simple end‐groups such as Boc and pyridine, the R 2 /R 3 interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.","journal":"Chemical Biology & Drug Design","year":2025,"id":551123,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":404859,"name":"Irina F. Sevrioukova","orcid":"0000-0002-4498-6057","position":1,"is_corresponding":false},{"id":404858,"name":"Eric R. Samuels","orcid":"0000-0001-7888-1870","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:54:20.915388Z","pmid":"39792691","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}