Binding of pyrazole-based inhibitors to Mycobacterium tuberculosis pantothenate synthetase: docking and MM-GB(PB)SA analysis
Binding of pyrazole-based inhibitors to Mycobacterium tuberculosis pantothenate synthetase: docking and MM-GB(PB)SA analysis
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DOI：
10.1039/c3mb70449a
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发表时间：
2014-01-01
影响因子：
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通讯作者：
Megnassan, Eugene
中科院分区：
文献类型：
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作者：
Ntie-Kang, Fidele;Kannan, Srinivasaraghavan;Megnassan, Eugene
最近，寻找抗结核新药一直是一个热门话题，寻找针对已知药物靶点和途径以外的有效药物靶点和途径的新抑制剂被认为是最有希望的前进方向。结核分枝杆菌泛酸合成酶(MTBPS)恰好是这样的靶点之一。为了对MTBPS的活性抑制剂进行虚拟筛选，并获得针对这一靶点的新抑制剂的设计思路，我们将一组基于吡唑的抑制剂对接到该酶的活性部位。使用MM-PB(GB)SA方法和分子动力学模拟对对接溶液进行了后处理，以分析和验证先前提出的两种结合模式。结果表明，MM-PBSA和MM-GBSA均能区分活性和非活性化合物。此外，基于药效团的评分方法在区分活性化合物和非活性化合物方面被证明是有效的。根据这项工作，已经设计了一种从商业数据库中筛选该酶的潜在抑制剂的方案。
Recently, the search for new drugs against tuberculosis (TB) has been a hot topic and the search for new inhibitors against validated drug targets and pathways other than those currently targeted by known drugs is suggested to be the most promising way forward. Mycobacterium tuberculosis pantothenate synthetase (MTBPS) happens to be one of such targets. In a quest to carry out virtual screening for active inhibitors against MTBPS and to get ideas for the design of new inhibitors against this target, we have docked a set of pyrazole-based inhibitors to the active site of this enzyme. The docking solutions were post processed using the MM-PB(GB) SA method and molecular dynamic simulations in order to analyze and validate the two previously proposed binding modes. The results show that both the MM-PBSA and MM-GBSA were able to discriminate between active and inactive compounds. Moreover, the pharmacophore-based scoring method proved efficient in discriminating the active compounds from inactives. From this work a protocol for screening of potential inhibitors of the enzyme from commercially available databases has been devised.