Mechanism Study And Molecular Design Of Mycobacterium Tuberculosis GyrB Inhibitors

Since ancient times,the survival and development of human beings have been threatened by disease.In practice,human beings constantly explore methods to heal illness where drug therapy plays a key role.With the rapid development of science and technology,modern drug research methods have been constantly updated.In traditional drug design,the probability of finding novel drugs is generally low,making it time-consuming and cost-ineffective.This is the point at which CADD(Computer Aided Drug Design)comes into play.CADD application of computer algorithms which can shorten the drug research and development cycle improves the efficiency of drug research and development.CADD has played a pivotal role in development of medically important molecules over the last three decades.In the part of introduction,the global background and research progress and existing inhibitors of pulmonary tuberculosis are briefly introduced.Second,the basic theory of CADD is described.In the second chapter,tuberculosis(TB)is an infectious disease that caused a number of deaths,so the development of new,safer and more efficacious TB inhibitors/drugs has become a necessity and a great challenge.Mycobacterium tuberculosis DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of anti-tubercular drug discovery.To design novel and potent MTB inhibitors,we performed molecular modeling studies which combined with 3D-QSAR,molecular docking,molecular dynamics simulations,and binding free energy calculations.48 quinoline-aminopiperidine inhibitors that act on DNA gyrase B subunit were used for constructing 3D-QSAR models.The results show that the best CoMFA model has high performance with q~2=0.643,r~2=0.947,and the best CoMSIA model with q~2=0.536,r~2=0.948.The contour map was in good agreement with the docking and molecular dynamics simulations which strongly demonstrates that the molecular modeling is reliable.Based on this information,several new compounds were designed and their inhibitory activities were also verified by the proposed models and ADME/T predictions.We hope that our research could bring new ideas to facilitate the development of novel inhibitors with higher inhibitory activity for TB.Chapter three,Mycobacterium tuberculosis DNA gyrase is the structure of A2B2,while the sel6 molecular has been shown to inhibit only B subunit.The selective inhibition mechanism of GyrA/GyrB by inhibitors was studied by molecular modeling methods such as molecular docking,molecular dynamics simulation and binding free energy decomposition.The binding modes of GyrA/GyrB and inhibitors were compared and analyzed in terms of structure and binding energy,and their binding mechanisms were summarized.The key factors causing the strong selectivity of GyrB were obtained.So this study can provide a direction for further research and development of medicines for treating tuberculosis.Chapter four,quantitative structure activity relationship(QSAR)model was bulit to predict the activity of 171 potential inhibitors.In this study,the linear genetic function approximation(GFA)was used to select descriptors,and the partial least squares(PLS)was used to establish a regression model.The most model-contributing descriptors were selected by sorting the variable importance in projection(VIP)values of the initial variables to reveal the influencing factors of the inhibitory activity of the compounds,so as to provide a theoretical basis for the synthesis of more effective and higher inhibitory activity of Mycobacterium tuberculosis inhibitors.