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Discovering novel Cathepsin L inhibitors from natural products using artificial intelligence

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收录情况： ◇ SCIE

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机构： [1]Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. [2]Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China.

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关键词： Cathepsin L Deep learning Molecule docking Natural product Enzyme kinetics

摘要：

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.© 2024 The Authors.

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出版当年[2023]版：

大类 | 2 区生物学

小类 | 3 区生化与分子生物学

最新[2023]版：

大类 | 2 区生物学

小类 | 3 区生化与分子生物学

JCR分区：

出版当年[2022]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

最新[2023]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

影响因子： 4.5 最新[2023版] 5.1 最新五年平均 6 出版当年[2022版] 6.3 出版当年五年平均 6.155 出版前一年[2021版] 4.5 出版后一年[2023版]

第一作者：

第一作者机构： [1]Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. [2]Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China.

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通讯作者：

通讯机构： [1]Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China. [2]Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China.

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