In silico screening of Fyn kinase inhibitors using classification-based QSAR model, molecular docking, molecular dynamics and ADME study.

Autor: Hang NT; Department of Pharmacognosy, Faculty of Pharmacognosy and Traditional Medicine, Hanoi University of Pharmacy, Hanoi, 11000, Vietnam., Anh TDH; Department of Pharmacognosy, Faculty of Pharmacognosy and Traditional Medicine, Hanoi University of Pharmacy, Hanoi, 11000, Vietnam., Thanh LN; Department of Analytical Chemistry and Standardization, National Institute of Medicinal Materials, 3B Quang Trung, Hanoi, 10000, Vietnam., Anh NV; Institute of Information Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, 10000, Vietnam., Van Phuong N; Department of Pharmacognosy, Faculty of Pharmacognosy and Traditional Medicine, Hanoi University of Pharmacy, Hanoi, 11000, Vietnam. phuongnv@hup.edu.vn.
Jazyk: angličtina
Zdroj: Molecular diversity [Mol Divers] 2024 Aug; Vol. 28 (4), pp. 2217-2228. Date of Electronic Publication: 2024 Jun 17.
DOI: 10.1007/s11030-024-10905-w
Abstrakt: This study aimed to use a computational approach that combined the classification-based QSAR model, molecular docking, ADME studies, and molecular dynamics (MD) to identify potential inhibitors of Fyn kinase. First, a robust classification model was developed from a dataset of 1,078 compounds with known Fyn kinase inhibitory activity, using the XGBoost algorithm. After that, molecular docking was performed between potential compounds identified from the QSAR model and Fyn kinase to assess their binding strengths and key interactions, followed by MD simulations. ADME studies were additionally conducted to preliminarily evaluate the pharmacokinetics and drug-like characteristics of these compounds. The results showed that our obtained model exhibited good predictive performance with an accuracy of 0.95 on the test set, affirming its reliability in identifying potent Fyn kinase inhibitors. Through the application of this model in conjunction with molecular docking and ADME studies, nine compounds were identified as potential Fyn kinase inhibitors, including 208 (ZINC70708110), 728 (ZINC8792432), 734 (ZINC8792187), 736 (ZINC8792350), 738 (ZINC8792286), 739 (ZINC8792309), 817 (ZINC33901069), 852 (ZINC20759145), and 1227 (ZINC100006936). MD simulations further demonstrated that the four most promising compounds, 728, 734, 736, and 852 exhibited stable binding with Fyn kinase during the simulation process. Additionally, a web-based platform ( https://fynkinase.streamlit.app/ ) has been developed to streamline the screening process. This platform enables users to predict the activity of their substances of interest on Fyn kinase from their SMILES, using our classification-based QSAR model and molecular docking.
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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