Virtual Screening For Lead Compounds To Anti-drug Resistant Tuberculosis Based On Three Targets

Since the discovery of tuberculosis in the 1880 s,it has seriously affected people’s survival and quality of life.In recent years,the emergence of drug-resistant M.tuberculosis and super-drug resistant M.tuberculosis with drug use has made the existing anti-tuberculosis drugs have serious challenges.Currently,one of the research and development priorities for anti-drug resistant TB is to obtain new drug targets and specific lead compounds for this target.In this study,we targeted Isocitrate Lyase(ICL),Thymidylate kinase(TMK),and Pantothenate Synthetase(PS)through structure-based virtual screening and molecular Kinetic simulations to discover inhibitors of ICL,TMK,and PS,and to obtain promising lead compounds for the treatment of drug-resistant tuberculosis.In the first part,the binding ability of 53399 compounds in the Maybrige database to ICL,TMK and PS targets was evaluated by molecular docking as the main means by virtual screening based on target structure.In the second part,for each target,the top 10 candidate compounds were retained and the binding mode of the compound to the target was discussed.Subsequently,we selected three candidate compounds that were optimally scored in the virtual screening results of i ICL,TMK and PS(Marbrige ID: Compound19257、Compound11701、Compound22558)for molecular dynamics simulation and Combined with the calculation of free energy,the interaction mode and mechanism of the above compounds with the target are elucidated from the perspective of energy and structure.The results showed that the hydrogen bonding,π-π conjugate and π-δ conjugate of candidate compounds were beneficial to the stable binding of the target.In summary,the results of this study have certain theoretical value for the design and development of anti-tuberculosis drugs targeting ICL,TMK and PS.