Li Qi, Zhou Si-Rui, Kim Hanna, Wang Hao, Zhu Juan-Juan, Yang Jin-Kui
Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China.
Comput Struct Biotechnol J. 2024 Jun 7;23:2606-2614. doi: 10.1016/j.csbj.2024.06.009. eCollection 2024 Dec.
Cathepsin L (CTSL) is a promising therapeutic target for metabolic disorders. Current pharmacological interventions targeting CTSL have demonstrated potential in reducing body weight gain, serum insulin levels, and improving glucose tolerance. However, the clinical application of CTSL inhibitors remains limited. In this study, we used a combination of artificial intelligence and experimental methods to identify new CTSL inhibitors from natural products. Through a robust deep learning model and molecular docking, we screened 150 molecules from natural products for experimental validation. At a concentration of 100 µM, we found that 36 of them exhibited more than 50 % inhibition of CTSL. Notably, 13 molecules displayed over 90 % inhibition and exhibiting concentration-dependent effects. The molecular dynamics simulation on the two most potent inhibitors, Plumbagin and Beta-Lapachone, demonstrated stable interaction at the CTSL active site. Enzyme kinetics studies have shown that these inhibitors exert an uncompetitive inhibitory effect on CTSL. In conclusion, our research identifies Plumbagin and Beta-Lapachone as potential CTSL inhibitors, offering promising candidates for the treatment of metabolic disorders and illustrating the effectiveness of artificial intelligence in drug discovery.
组织蛋白酶L（CTSL）是代谢紊乱一个很有前景的治疗靶点。目前针对CTSL的药物干预已显示出在减轻体重增加、降低血清胰岛素水平和改善糖耐量方面的潜力。然而，CTSL抑制剂的临床应用仍然有限。在本研究中，我们结合人工智能和实验方法从天然产物中鉴定新的CTSL抑制剂。通过一个强大的深度学习模型和分子对接，我们从天然产物中筛选了150个分子进行实验验证。在100µM的浓度下，我们发现其中36个分子对CTSL的抑制率超过50%。值得注意的是，13个分子表现出超过90%的抑制率并呈现浓度依赖性效应。对两种最有效的抑制剂白花丹素和β-拉帕醌进行的分子动力学模拟表明，它们在CTSL活性位点有稳定的相互作用。酶动力学研究表明，这些抑制剂对CTSL发挥非竞争性抑制作用。总之，我们的研究确定白花丹素和β-拉帕醌为潜在的CTSL抑制剂，为代谢紊乱的治疗提供了有前景的候选药物，并说明了人工智能在药物发现中的有效性。
