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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Multicomplex-based pharmacophore modeling in conjunction with multi-target docking and molecular dynamics simulations for the identification of PfDHFR inhibitors
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Multicomplex-based pharmacophore modeling in conjunction with multi-target docking and molecular dynamics simulations for the identification of PfDHFR inhibitors

机译：基于多络合物的药种模型与多目标对接和分子动力学模拟进行鉴定的PFDHFR抑制剂

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Plasmodium falciparum dihydrofolate reductase enzyme (PfDHFR) is counted as one of the attractive and validated antimalarial drug targets. However, the point mutations in the active site of wild-type PfDHFR have developed resistance against the well-known antifolates. Therefore, there is a dire need for the development of inhibitors that can inhibit both wild-type and mutant-type DHFR enzyme. In the present contribution, we have constructed the common feature pharmacophore models from the available PfDHFR. A representative hypothesis was prioritized and then employed for the screening of natural product library to search for the molecules with complementary features responsible for the inhibition. The screened candidates were processed via drug-likeness filters and molecular docking studies. The docking was carried out on the wild-type PfDHFR (3QGT); double-mutant PfDHFR (3UM5 and 1J3J) and quadruple-mutant PfDHFR (1J3K) enzymes. A total of eight common hits were obtained from the docking calculations that could be the potential inhibitors for both wild and mutant type DHFR enzymes. Eventually, the stability of these candidates with the selected proteins was evaluated via molecular dynamics simulations. Except for SPECS14, all the prioritized candidates were found to be stable throughout the simulation run. Overall, the strategy employed in the present work resulted in the retrieval of seven candidates that may show inhibitory activity against PfDHFR and could be further exploited as a scaffold to develop novel antimalarials. Communicated by Ramaswamy H. Sarma
机译：疟原虫二羟氢醇还原酶酶（PFDHFR）被计数为有吸引力和验证的抗疟药靶标的。然而，野生型PFDHFR的活性位点中的点突变对众所周知的防冻物产生了抗性。因此，急需开发可抑制野生型和突变型DHFR酶的抑制剂的需求。在目前的贡献中，我们从可用的PFDHFR构建了常见的特征药物模型。优先考虑代表性假设，然后用于筛选天然产物文库，以寻找具有负责抑制的互补特征的分子。通过药物相似过滤器和分子对接研究加工筛选的候选物。对接是在野生型PFDHFR（3QGT）上进行的;双突变体PFDHFR（3um5和1J3j）和四重突变体PFDHFR（1J3K）酶。从对接计算中获得总共八个常见命中，这可能是野生和突变型DHFR酶的潜在抑制剂。最终，通过分子动力学模拟评估这些候选物与所选蛋白质的稳定性。除SPECS14外，在整个模拟运行过程中发现所有优先考虑的候选人都被发现稳定。总体而言，本工作中所采用的策略导致七个候选人检索可能表现出对PFDHFR的抑制活动，并且可以进一步利用作为踏手，以发展新的抗疟药。由Ramaswamy H. Sarma沟通

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