Identification of potential FAK inhibitors using mol2vec molecular descriptor-based QSAR, molecular docking, ADMET study, and molecular dynamics simulation

• Published in: Molecular diversity Vol. 28; no. 4; pp. 2163 - 2175
• Main Authors: Hang, Nguyen Thu, My, Than Thi Kieu, Van Anh, Le Thi, Van Anh, Phan Thi, Anh, Thai Doan Hoang, Van Phuong, Nguyen
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2024; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Kinases; Life Sciences; Organic Chemistry; Original Article; Pharmacy; Polymer Sciences; Simulation; Molecular dynamics; FAK; Docking; QSAR; mol2vec
• ISSN: 1381-1991; 1573-501X; 1573-501X
• DOI: 10.1007/s11030-024-10839-3

This study aims to identify potential focal adhesion kinase (FAK) inhibitors through an integrated computational approach, combining mol2vec descriptor-based QSAR, molecular docking, ADMET study, and molecular dynamics simulation. A dataset of 437 compounds with known FAK inhibitory activities was used to develop QSAR models using machine learning algorithms combined with mol2vec descriptors. Subsequently, the most promising compounds were subjected to molecular docking against FAK to evaluate their binding affinities and key interactions. ADMET study and molecular dynamics simulation were also employed to investigate the pharmacokinetic, drug-like properties, and the stability of the protein–ligand complexes. The results showed that the mol2vec descriptor-based QSAR model established by support vector regression demonstrated good predictive performance (R 2  = 0.813, RMSE = 0.453, MAE = 0.263 in case of training set, and R 2  = 0.729, RMSE = 0.635, MAE = 0.477 in case of test set), indicating their reliability in identifying potent FAK inhibitors. Using this QSAR model and molecular docking, compound 21 (ZINC000004523722) was identified as the most potential compound, with predicted logIC 50 value and binding energy of 2.59 and − 9.3 kcal/mol, respectively. The results of molecular dynamics simulation and ADMET study also further suggested its potential as a promising drug candidate. However, because our research was merely theoretical, additional in vitro and in vivo studies are required for the verification of these results.