Structural insight into <i>Mycobacterium tuberculosis</i> maltosyl transferase inhibitors: pharmacophore-based virtual screening, docking, and molecular dynamics simulations

Pharmacophore-based virtual screening, subsequent docking, and molecular dynamics (MD) simulations have been done to identify potential inhibitors of maltosyl transferase of <i>Mycobacterium tuberculosis</i> (mtb GlgE). Ligand and structure-based pharmacophore models representing its primary binding site (pbs) and unique secondary binding site 2 (sbs2), respectively, were constructed based on the three dimensional structure of mtb GlgE. These pharmacophore models were further used for screening of ZINC and antituberculosis compounds database (ATD). Virtually screened molecules satisfying Lipinski’s rule of five were then analyzed using docking studies and have identified 23 molecules with better binding affinity than its natural substrate, maltose. Four top scoring ligands from ZINC and ATD that either binds to pbs or sbs2 have been subjected to 10 ns each MD simulations and binding free energy calculations. Results of these studies have confirmed stable protein ligand binding. Results reported in the article are likely to be helpful in antitubercular therapeutic development research.本研究通过基于药效团（pharmacophore）的虚拟筛选、后续分子对接以及分子动力学（MD）模拟，旨在鉴定结核分枝杆菌（Mycobacterium tuberculosis）麦芽糖基转移酶（mtb GlgE）的潜在抑制剂。分别基于mtb GlgE的三维结构，构建了对应其主要结合位点（pbs）与独特次级结合位点2（sbs2）的基于配体与基于结构的药效团模型。利用上述药效团模型对ZINC数据库与抗结核化合物数据库（ATD）进行虚拟筛选，随后对满足类药五规则（Lipinski’s rule of five）的虚拟筛选命中分子开展分子对接分析，最终鉴定出23个结合亲和力优于其天然底物麦芽糖的分子。从ZINC与ATD数据库中筛选出的4个结合于pbs或sbs2的高分配体，分别进行了时长为10 ns的MD模拟与结合自由能计算。上述研究结果证实了蛋白-配体结合的稳定性。本文所报道的研究结果有望为抗结核治疗开发相关研究提供助力。