3D-QSAR And Virtual Screening Study Of TNNâ… 3K Inhibitors

Cardiac troponin I-interacting kinase(TNNâ… 3K)is an emerging target for heart disease.Studies have shown that reduced expression level of TNNâ… 3K has a protective effect on the heart.Potential TNNâ… 3K inhibitors were designed by computer aided drug design.The results obtained are expected to lay the theoretical foundation for the development of high activity TNNâ… 3K inhibitors.In this study,Co MFA,Co MSIA and Topomer Co MFA models were constructed with a series of TNNâ… 3K inhibitors to investigate the structure-activity relationship.The cross-validate regression coefficients(q~2)of Co MFA,Co MSIA and Topomer Co MFA models were 0.654,0.67 and 0.623 respectively,the non-cross-validate regression coefficients(r~2)were 0.978,0.961 and 0.951 respectively,and the external validation coefficients(r~2pred)were 0.582,0.666 and 0.553 respectively,these parameters indicate that these models are favorably stable and predictable.20 pharmacophore models were constructed following the GALAHAD method using7 molecules with high activity.Model 008 showed best results which included three hydrophobic centers,three hydrogen bond donors,and seven hydrogen bond acceptors.The binding mode of TNNâ… 3K and its ligand was studied by molecular docking and the docking results were further validate by molecular dynamics simulations.The results showed that Ile542 and Thr539 were the key amino acids when TNNâ… 3K interacts with its ligand.In addition,if the ligand interacts with Asp606,the ligand may have high activities.The ZINC database was searched by the combination of Topomer Search,pharmacophore-based virtual screening,and molecular docking.Topomer Search was utilized for virtual screening in ZINC database,and 49 new molecules were obtained,but only 22 molecules were obtained after pharmacophore-based virtual screening.Finally,7molecules were screened by molecular docking as the potential inhibitors,which exhibited higher activity compared with the training set molecules.