Samuels Eric R, Sevrioukova Irina F
Department of Pharmaceutical Sciences, University of California, Irvine, California, USA.
Department of Molecular Biology and Biochemistry, University of California, Irvine, California, USA.
Chem Biol Drug Des. 2025 Jan;105(1):e70043. doi: 10.1111/cbdd.70043.
A new series of 13 ritonavir-like inhibitors of human drug-metabolizing CYP3A4 was rationally designed to study the R side-group and R end-group interplay when the R side-group is represented by phenyl. Spectral, functional, and structural characterization showed no improvement in the binding affinity and inhibitory potency of R/R-phenyl inhibitors upon elongation and/or fluorination of R-Boc (tert-butyloxycarbonyl) or its replacement with benzenesulfonyl. When R is pyridine, the impact of R-phenyl-to-indole/naphthalene substitution was multidirectional and highly dependent on side-group stereo configuration. Overall, the R-naphthalene/R-pyridine containing 2f (R/S) was the series lead compound and one of the strongest binders/inhibitors designed thus far (K = 0.009 μM; IC = 0.10 μM). Introduction of a larger biphenyl or fluorene as R did not lead to any improvements. Contrarily, fluorene-containing 13 was the series weakest binder and inhibitor (K = 0.734 μM; IC = 1.32 μM), implying that the fluorene moiety is too large to allow unrestricted access to the active site. The R-biphenyl, however, can switch positions with R-Boc to enable heme ligation. Thus, for small and chemically simple end-groups such as Boc and pyridine, the R/R interplay could lead to conformational rearrangement that would be difficult to foresee without structural information.
合理设计了一系列新的13种类似利托那韦的人药物代谢CYP3A4抑制剂，以研究当R侧基由苯基表示时R侧基和R端基的相互作用。光谱、功能和结构表征表明，在R-Boc（叔丁氧羰基）延长和/或氟化或用苯磺酰基取代后，R/R-苯基抑制剂的结合亲和力和抑制效力没有改善。当R为吡啶时，R-苯基到吲哚/萘取代的影响是多方向的，并且高度依赖于侧基立体构型。总体而言，含R-萘/R-吡啶的2f（R/S）是该系列的先导化合物，也是迄今为止设计的最强结合剂/抑制剂之一（K = 0.009 μM；IC = 0.10 μM）。引入更大的联苯或芴作为R并没有带来任何改善。相反，含芴的13是该系列中最弱的结合剂和抑制剂（K = 0.734 μM；IC = 1.32 μM），这意味着芴部分太大，无法无限制地进入活性位点。然而，R-联苯可以与R-Boc交换位置以实现血红素连接。因此，对于诸如Boc和吡啶等小且化学结构简单的端基，R/R相互作用可能导致构象重排，而没有结构信息很难预见这种重排。
