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Identification of potential extracellular signal-regulated protein kinase 2 inhibitors based on multiple virtual screening strategies

Affiliation
Department of Acupuncture, Affiliated Hospital of Shandong University of Traditional Chinese Medicine ,Jinan ,China
Yang, Ruoqi;
Affiliation
Institute of Chinese Materia Medica ,China Academy of Chinese Medical Sciences ,Beijing ,China
Zhao, Guiping;
Affiliation
Department of Ultrasound, Jinan Central Hospital Affiliated to Shandong First Medical University ,Jinan ,China
Zhang, Lili;
Affiliation
School of Pharmacy ,Shandong University of Traditional Chinese Medicine ,Jinan ,China
Xia, Yu;
Affiliation
School of Pharmacy ,Shandong University of Traditional Chinese Medicine ,Jinan ,China
Yu, Huijuan;
Affiliation
School of Pharmacy ,Shandong University of Traditional Chinese Medicine ,Jinan ,China
Yan, Bin;
Affiliation
Department of Acupuncture, Affiliated Hospital of Shandong University of Traditional Chinese Medicine ,Jinan ,China
Cheng, Bin

The integration of multiple virtual screening strategies facilitates the balance of computational efficiency and prediction accuracy. In this study, we constructed an efficient and reliable “multi-stage virtual screening-in vitro biological validation” system to identify potential inhibitors targeting extracellular signal-regulated protein kinase 2 (ERK2). Firstly, we rapidly obtained 10 candidate ERK2 inhibitors with desirable pharmacokinetic characteristics from thousands of named natural products in ZINC database based on machine learning classification models and ADME/T prediction. The structure-based molecular docking approach was then used to obtain four further hits with lower binding free energy compared to the positive control molecule Magnolipin. Subsequently, the two compounds were purchased for in vitro biological validation considering commercial availability and economic cost, and the results showed that Dodoviscin A exhibited acceptable inhibitory activity on ERK2 (IC 50 = 10.79 μm). Finally, the mechanism of action and binding stability of this natural product inhibitor were investigated by binding mode analysis and molecular dynamics simulation.

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License Holder: Copyright © 2022 Yang, Zhao, Zhang, Xia, Yu, Yan and Cheng.

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