Journal
ARABIAN JOURNAL OF CHEMISTRY
Volume 14, Issue 6, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.arabjc.2021.103144
Keywords
FAK; CoMFA; CoMSIA; Molecular docking; Molecular dynamics
Categories
Funding
- National Natural Science Foundation of China [32001699]
- Shandong Provincial Natural Science Foundation of China [ZR2019BC102]
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Through 3D-QSAR and molecular dynamics simulations, the structure-activity relationships and mechanism of actions of FAK inhibitors were investigated, predicting the inhibitory activities of novel inhibitors and guiding the optimization of FAK inhibitors with higher inhibitory activities.
Focal adhesion kinase (FAK) is a promising target for developing more effective anticancer drugs. To better understand the structure-activity relationships and mechanism of actions of FAK inhibitors, a molecular modeling study using 3D-QSAR, molecular docking, molecular dynamics simulations, and binding free energy analysis were conducted. Two types of satisfactory 3D-QSAR models were generated, comprising the CoMFA model (R-cv(2) = 0.528, R-pred(2) = 0.7557) and CoMSIA model (R-cv(2) = 0.757, R-pred(2) = 0.8362), for predicting the inhibitory activities of novel inhibitors. The derived contour maps indicate structural characteristics for substituents on the template. Molecular docking, molecular dynamic simulations and binding free energy calculations further reveal that the binding of inhibitors to FAK is mainly contributed from hydrophobic, electrostatic and hydrogen bonding interactions. In addition, some key residues (Arg14, G1u88, Cys90, Arg138, Asn139, Leu141, and Leu155) responsible for ligand-receptor binding are highlighted. All structural information obtained from 3D-QSAR models and molecular dynamics is consist with the available experimental activities. All the results will facilitate the optimization of this series of FAK inhibitors with higher inhibitory activities. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.
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