{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T12:19:45Z","timestamp":1753877985740,"version":"3.41.2"},"reference-count":43,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100006955","name":"Office of Extramural Research","doi-asserted-by":"publisher","award":["ES025767"],"award-info":[{"award-number":["ES025767"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>A new series of 13 ritonavir\u2010like inhibitors of human drug\u2010metabolizing CYP3A4 was rationally designed to study the R<jats:sub>2<\/jats:sub> side\u2010group and R<jats:sub>3<\/jats:sub> end\u2010group interplay when the R<jats:sub>1<\/jats:sub> side\u2010group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R<jats:sub>1<\/jats:sub>\/R<jats:sub>2<\/jats:sub>\u2010phenyl inhibitors upon elongation and\/or fluorination of R<jats:sub>3<\/jats:sub>\u2010Boc (tert\u2010butyloxycarbonyl) or its replacement with benzenesulfonyl. When R<jats:sub>3<\/jats:sub> is pyridine, the impact of R<jats:sub>2<\/jats:sub>\u2010phenyl\u2010to\u2010indole\/naphthalene substitution was multidirectional and highly dependent on side\u2010group stereo configuration. Overall, the R<jats:sub>2<\/jats:sub>\u2010naphthalene\/R<jats:sub>3<\/jats:sub>\u2010pyridine containing <jats:bold>2f<\/jats:bold> (<jats:italic>R<\/jats:italic>\/<jats:italic>S<\/jats:italic>) was the series lead compound and one of the strongest binders\/inhibitors designed thus far (<jats:italic>K<\/jats:italic><jats:sub>s<\/jats:sub>\u2009=\u20090.009\u2009\u03bcM; IC<jats:sub>50<\/jats:sub>\u2009=\u20090.10\u2009\u03bcM). Introduction of a larger biphenyl or fluorene as R<jats:sub>2<\/jats:sub> did not lead to any improvements. Contrarily, fluorene\u2010containing <jats:bold>13<\/jats:bold> was the series weakest binder and inhibitor (<jats:italic>K<\/jats:italic><jats:sub>s<\/jats:sub>\u2009=\u20090.734\u2009\u03bcM; IC<jats:sub>50<\/jats:sub>\u2009=\u20091.32\u2009\u03bcM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R<jats:sub>2<\/jats:sub>\u2010biphenyl, however, can switch positions with R<jats:sub>3<\/jats:sub>\u2010Boc to enable heme ligation. Thus, for small and chemically simple end\u2010groups such as Boc and pyridine, the R<jats:sub>2<\/jats:sub>\/R<jats:sub>3<\/jats:sub> interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.<\/jats:p>","DOI":"10.1111\/cbdd.70043","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T19:11:21Z","timestamp":1736536281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of Larger Side\u2010Group Functionalities and the Side\/End\u2010Group Interplay in Ritonavir\u2010Like Inhibitors of <scp>CYP3A4<\/scp>"],"prefix":"10.1111","volume":"105","author":[{"given":"Eric R.","family":"Samuels","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of California  Irvine California 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