Homology Modeling Of Mtb＿G5K And Its Docking Mode With[3,2-c] Quinolone

BackgroundTuberculosis(TB)is a deadly infectious disease caused by the Mycobacterium Tuberculosis(Mtb).The emergence of drug-resistant strains in the human population has made the treatment more complex.Therefore,it is necessary to develop novel anti-TB drugs with novel mechanisms of action to limit cross-resistance.[3,2-c] quinoline activator can activate novel target Glutamate 5-kinase(G5K),and then feedback inhibit Mtb strains,which may be the direction for the development of novel anti-tuberculosis drugs.It is of great significance to explore the binding mode of small quinoline molecules with Mtb,analyze the mechanism of action at the molecular level and design new enzyme activating drugs.Objective1.Mtb＿G5K was docked with [3,2-c] quinoline compounds,the binding orientation and hydrogen bond were analyzed,and the modeling Mtb＿G5K and the complex were simulated by MD,to verify the correctness of the binding sites,and refine the analysis of the change of the binding mode under the action of solvation,which provides a theoretical basis for the design of enzyme activated targeted drugs.2.Designed novel compounds of enzyme-activated type of [3,2-c] quinoline and combined with the docking results to further analyze the reasons affecting the activator activity.Method1.The target sequences were searched through NCBI database,and the appropriate template proteins were screened out.The Mtb＿G5K models were established by MOE and Modeller software respectively.2.PROCHECK、Verify-3D and ERRAT were used to score and evaluate the modeling results of the two software from skeleton to side chain.3.Sybyl-X2.0 was used to prepare the protein of the reasonable model,and drawn the[3,2-c] quinoline small molecules.Auto Dock was used for molecular docking,and the conformation with the most stable classification orientation was selected from the 30 conformations generated for analysis.The dynamics simulation was carried out in Amber18.4.HY33 series small molecules were designed according to the results of docking and dynamics simulation analysis.Auto Dock was used for docking.Results1.According to Mtb＿G5K sequence in NCBI database,2J5 T was selected as template protein,and homologous modeling was carried out in MOE and Modeller software respectively.2.After quantitative analysis of the distribution of carbon atoms in the skeleton,the modeling results in Modeller were selected as the target,and the side chains were further analyzed.The final evaluation results prove that the Mtb＿G5K modeled by Modeller was reasonable.3.Docking showed that the next step in the modification of small molecules could focus on the protection and modification of amino groups,and kinetic simulation also verifies that the docking complex was stable around the binding pocket.4.Five [3,2-c] quinoline compounds: HY33-1,HY33-2,HY33-3,HY33-4 and HY33-5,were designed.HY33-1 has highest activity in their docking results,which has the potential to become a novel enzyme-activated anti-tuberculosis drug.ConclusionFive quinoline small molecules were designed,and three of them showed high predictive activity.The modification of [3,2-c] quinoline molecules provided the idea for the design of novel enzyme active drugs.It was found that the hydrogen bond formed between Ala-60 and nitrogen heteroatom has a great influence on the activity.The interaction between molecules and Ser-28 also has a great effect on stability.