The Molecular Design And Molecular Dynamics Simulation Study Of ALK5 Inhibitors

Transforming growth factorβ（TGF-β）is the superfamily of cytokines which are pleiotropic modulators of extracellular matrix production,immunosuppression,and epithelial-mesenchymal transition（EMT）.In this way,inhibition of TGF-βis a good strategy to treat many kinds of cancer and fibrotic diseases.Transforming growth factor typeβreceptor I（ALK5）is kinase associated with a wide variety of pathological processes.ALK5 has been regarded as the target in treatments of a variety of cancers and fibrosis diseases,as it plays an important role in the signaling pathway of TGF-β.However,p38 mitogen activated protein kinase（p38MAPK）and ALK5 are highly homologous in protein sequences.As a result,when ALK5inhibitors are inhibiting ALK5,they may also inhibit p38 MAPK.Currently,it has not yet been reported that the inhibitory effect of these inhibitors on p38MAPK leads to whether dual inhibitory effect or side effect.Therefore,it is important to develop highly selective ALK5 inhibitors.Recently a series of compounds have been synthesized as ALK5 inhibitors.However,the study of their interaction mechanism and selectivity against other potential targets remains elusive.In this research,a dataset of ALK5 inhibitors were collected and studied based on the combination of2D-QSAR,molecular docking,molecular dynamics simulation and binding free energy calculation.The quality of QSAR models were assessed statistically by F,R²and R²_ADJ,proved to be credible.The cross validations for the models(q²_LOO=0.571and 0.629,respectively)showed their robustness,while the external validations(r²_test=0.703 and 0.764,respectively)showed their predictive power.Besides,the predicted binding free energy results calculated by Molecular Mechanics/Generalized Born Surface Area method（MM/GBSA）were in accordance with the experimental data,and the van der Waals energy term was the factor that had the most significant impact on ligand binding.What is more,several important residues（Val219,Lys232,Tyr282,His283,Leu340 and Asp351）were found to significantly affect the binding affinity.Finally,based on our analyses above,a proposed series of molecules were designed.