Design Of S6K1 Inhibitors By Molecular Docking And Molecular Dynamics Simulations

Studies have shown that S6K1 has become an attractive therapeutic target in developing medicines for the treatment of obesity,type 2 diabetes and cancer.In this paper,the S6K1 inhibitors developed by Kablaoui Institute were used as the lead compound.Then three S6K1 inhibitors（D1-D3）with fluorine were designed and synthesized by molecular docking and molecular dynamics simulation.Finally,D1-D3 exhibited high S6K1 inhibitory activity after enzymatic inhibition test,which indicated that the obtained results from computational studies were useful to guide the design of novel S6K1 inhibitors.By docking compound Comp.1-5 with S6K1,it was found that the key residues around the ligand were Leu97,Ala121,Met225,Leu175 and Glu173 in the hinge region,Val105 and Leu172 in the hydrophobic pocket region,and Glu222 in the solvent exposed region.The key factors for the inhibitory activity of these inhibitors are hydrogen bonds and hydrophobic interactions.Then MM/GBSA free energy calculations of Comp.5 with S6K1 showed that van der Waals interaction(△G_VDW)contributed binding affinity(△G_bind)most(-54.6050kcal·mol^-1).And residues that significantly affected inhibitor activity were identified by free energy decomposition as Leu97,Val105,Ala121,Leu172,Glu173,Leu175,Glu222 and Met225.These results are consistent with the results of molecular docking.D1-D3 were synthesized by condensation reaction and Suzuki coupling reaction,then their biological activities were tested.The test data showed that the IC₅₀ value of D1 against S6K1 was 56.7 nmol?L^-1,the IC₅₀ value of D2 against S6K1 was 15.9 nmol?L^-1,the IC₅₀ value of D3 against S6K1 was 179 nmol?L^-1.They had good inhibitory activity against S6K1.Since D1-D3 have chiral centers,we have carried out chiral resolution of D1-D3,and developed a preparation method with multi-gram quantities of 6-methoxychroman-3-carboxylic acid through salt formation,acidolysis and recrystallization processes.It has the advantages of cheap raw materials,mild salt-forming conditions,simple synthesis process and low cost.