Departments of Pharmaceutical Sciences, University of California, Irvine, CA 92697-3900, United States.
Departments of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, United States.
Bioorg Med Chem. 2020 Mar 15;28(6):115349. doi: 10.1016/j.bmc.2020.115349. Epub 2020 Jan 31.
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 R side-group as phenyl or naphthalene and R as indole or naphthalene in different stereo configuration showed that (i) analogues with the R-naphthalene tend to bind tighter and inhibit CYP3A4 more potently than the R-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 R/R 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 (IC of 0.055-0.085 μM vs. 0.130 μM, respectively).
确定结构决定因素对于强效抑制药物代谢细胞色素 P450 3A4（CYP3A4）的抑制剂的开发可能会有助于开发更安全的药物和更有效的药物增强剂。我们利用合理的抑制剂设计来阐明利托那韦类似物的构效关系，利托那韦是一种高度有效的 CYP3A4 抑制剂，作为药物增强剂上市。对 R 侧基为苯基或萘基且 R 为吲哚或萘基且具有不同立体构型的化合物进行分析表明：（i）与 R-苯基/吲哚相比，具有 R-萘基的类似物往往具有更强的结合能力和更有效的抑制 CYP3A4 的作用；（ii）立体化学成为更重要的影响因素，因为大体积的侧基限制了优化蛋白质-配体相互作用的能力；（iii）R/R 构型与优先结合 CYP3A4 的关系复杂，取决于侧基功能/相互作用和骨干间距；（iv）三种抑制剂 5a-b 和 7d 优于利托那韦（IC分别为 0.055-0.085 μM 与 0.130 μM）。
