Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur Maharashtra, India.
SAR QSAR Environ Res. 2022 Mar;33(3):215-235. doi: 10.1080/1062936X.2022.2041724. Epub 2022 Feb 28.
The FDA granted expedited approval for Johnson and Johnson's Bedaquiline to treat pulmonary multidrug resistant tuberculosis on 28 December 2012 which is more common in China, Russian Federation and India. Bedaquiline is the first anti-tubercular drug approved by the FDA in the last 40 years, and it has become a cynosure in the circles of synthetic chemists researching new anti-tubercular drugs. Bedaquiline's highly lipophilic nature raises major concerns like suppression of the hERG gene, hepatotoxicity, and phospholipidosis despite its potential antitubercular profile. To address these toxicity concerns, in the present work, we have employed the structural optimization of Bedaquiline using the ADMETopt web server, which optimizes lead with scaffold hopping and ADMET screening. The ADMETopt web server yielded the 476 structures through optimization of three sites in Bedaquiline. Further, we have validated the optimized structures for their activity by performing molecular docking and molecular dynamics (MD) simulations against the mycobacterial ATP synthase enzyme and density functional theory (DFT) study further provides insight into the reactivity of the compounds. After screening and analysis, compound #449 was observed to be the most promising mycobacterial ATP synthase inhibitor with minimal cardiotoxicity, hepatotoxicity and phospholipidosis.
2012 年 12 月 28 日，美国食品药品监督管理局（FDA）批准强生公司的贝达喹啉用于治疗耐多药肺结核，这种药物在中国、俄罗斯联邦和印度更为常见。贝达喹啉是 FDA 在过去 40 年中批准的第一种抗结核药物，它已成为合成化学家研究新型抗结核药物领域的焦点。尽管贝达喹啉具有潜在的抗结核特性，但它高度亲脂的特性引起了人们对 hERG 基因抑制、肝毒性和磷脂沉积等主要问题的关注。为了解决这些毒性问题，在本工作中，我们使用 ADMETopt 网络服务器对贝达喹啉进行了结构优化，该服务器通过支架跳跃和 ADMET 筛选对先导化合物进行优化。ADMETopt 网络服务器通过优化贝达喹啉的三个部位，生成了 476 个结构。此外，我们通过对分枝杆菌 ATP 合酶酶进行分子对接和分子动力学（MD）模拟，对优化后的结构进行了活性验证，并进一步通过密度泛函理论（DFT）研究深入了解了化合物的反应性。经过筛选和分析，化合物#449 被观察到是最有前途的分枝杆菌 ATP 合酶抑制剂，具有最小的心脏毒性、肝毒性和磷脂沉积。
