Rational Design And Synthesis Of Nucleoside Antimicrobial Leaders Targeting MraY

Objectives Using the computer-aided approach to design,optimize and synthesis Capuramycin compounds that target MraY.In addition,searching antituberculous compounds,which possess novel action mechanism and antibacterial activity,through in vitro bio-activity assay.Methods By constructing the library of MraY targeting Capramycin compounds,build 3D-QSAR model with significant predictive ability for Capuramycin compounds.Combining 3D-QSAR and molecular docking methods,investigate the relationship between the structure of Capuramycin analogues and their MraY inhibitory activity and analyze the structural characteristics affecting the activity of the compound,then modify and optimize the structure.We use chemical methods to synthesize the newly designed compounds and screen the compounds for in vitro antibacterial activity through Mycobacterium tuberculosis H37 Rv.Results Use a set of 52 capuramycin derivatives for the 3D-QSAR model design,which was validated through 13 compounds.A highly predictive MFA model was obtained with cross-validation q2 of 0.398,and non-cross validation partial leastsquares(PLS)analysis showed a conventional R2 of 0.976 and R2 pred of 0.839.The model has an excellent predictive ability.Combining the 3D-QSAR and molecular docking studies,a number of new Capuramycin analogs with improved activities were designed.Based on the 3D-QSAR and molecular docking method,substituent modification of Capuramycin around the azepan-2-one was executed and 8 brand new anti-TB compounds were designed and synthesized.Through the model of 3DQSAR,the bio-activity of Capuramycin derivatives were tested,which improved compared to the original Capuramycin.Setting antituberculous drugs INH and RIF as positive controls,in vitro antituberculosis activity showed that compound S1 had the best anti-TB activity with MIC 12?g /m L.Conclusions By combining 3D-QSAR and molecular docking method,Capuramycin derivatives can be summarized as following:(1)a bulky and electropositive substitute at the azepan-2-one moiety disfavors activity;(2)small and electropositive substituents at the nucleoside 2'-OH improves bioactivity;(3)bulky substituents at the sugar hydroxyl may improve MraY inhibition.In summary,the designed newly Capuramycin analogs have higher activity than those used for the model design.The synthetic compound S1 had relatively good anti-TB activity against Mycobacterium tuberculosis H37 Rv.Thus,combined 3D-QSAR and molecular docking can be used as a guideline to design and predict new Capuramycin analogs for tuberculosis therapy.