Molecular Docking,3D-QSAR And Molecular Dynamics Simulation Of Mps1 Inhibitors

Monopole spindle 1(Mps1),a dual-specificity protein kinase,is one of the major components for spindle assembly checkpoint that plays a crucial role in mitosis.In addition to its role in mitosis,Mps1 also participates in centrosome replication,DNA damage checkpoint response,meiosis,etc.Studies have shown that Mps1 is overexpressed in a variety of cancer types,and cancer cells thus face pressure from abnormal chromosomes and centrosomes,but Mps1 is hardly expressed in normal cells.Hence the inhibition of Mps1 kinases activity by small molecular compounds seriously reduces the viability of cancer cells and has little effect on normal cells.Besides,Mps1 can enhance the sensitivity of tumor cell lines to chemotherapeutic drugs such as paclitaxel.Therefore,Mps1 has become a potential target for anticancer drug research.To date,a variety of Mps1 inhibitors have been developed.Mps1,like other kinase inhibitors,are competitive inhibitors,so Mps1 inhibitors not only inhibit Mps1but also inhibit proteins with high Mps1 identity,such as CDK2?Aroura A?Aroura B.Therefore,improving the selectivity of small molecules is the focus of research at this stage.There is a new class of pyrido[3,4-d]pyrimidine inhibitors with excellent potency and selectivity,but the binding mode of small molecule inhibitors and proteins has not been clearly explained.This paper,utilizing molecular docking,molecular dynamics simulation,energy calculation,and quantitative structure-activity relationship,explores the interaction mechanism between pyridinium and[3,4-d]pyrimidine,a novel inhibitor,and Mps1.From the results of the docking of 26 of these compounds and the analysis of the 200ns kinetic simulation of representational four of them,key amino acid residues in proteins Gly605 and Lys529 enhance binding strength by forming hydrogen bonds with inhibitors.The structure and shape of small molecular compounds are the keys to the important hydrophobic pocket.In the analysis of binding free energy,van der Waals force is the main force,and it reveals Ile531,Val539,Cys604,Gly605,Leu654,Ile663,Pro673 can form strong interaction with inhibitors.In this paper,the three-dimensional quantitative structure-activity relationship is used to construct different models,the association between structure and activity was obtained by different models.In modeling,some ways such as q~2(CoMFA 0.468;CoMSIA 0.725),r~2(CoMFA 0.925;CoMSIA 0.998),SEE,space,electrostatic,hydrophobic,hydrogen bond donor,and hydrogen bond acceptor field are used to verify the accuracy of the model.By analyzing and comparing the isopotential map of the CoMFA model,the effects of the properties of different groups on the activity of the compounds were gained.According to the analysis of the isopotential map of the CoMSIA model,the effects of different hydrophobicity and hydrogen bond on the activity of compounds were obtained.The new insights gained not only help to understand the binding patterns of Mps1 inhibitors,but also provide valuable guidance for the discovery of new anti-breast cancer drugs.