Molecular dynamics simulation and binding free energy studies of novel leads belonging to the benzofuran class inhibitors of Mycobacterium tuberculosis Polyketide Synthase 13
Molecular dynamics simulation and binding free energy studies of novel leads belonging to the benzofuran class inhibitors of Mycobacterium tuberculosis Polyketide Synthase 13
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DOI：
10.1080/07391102.2018.1462734
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发表时间：
2019-04-13
影响因子：
4.4
通讯作者：
Neto, A. M. J. C.
中科院分区：
文献类型：
--
作者：
Cruz, Jorddy N.;Costa, Jose F. S.;Neto, A. M. J. C.
在这项工作中，通过分子动力学模拟和自由能计算研究了新型聚酮合酶13（Pks13）抑制剂的结合机制。对属于苯并呋喃类的药物 Tam1 及其类似物进行 100 ns 模拟，根据均方根偏差获得的结果，所有模拟从大约 30 ns 开始收敛。为了分析骨架浮选，绘制了 C α 原子的均方根波动；分析表明，最大的波动发生在蛋白质盖子结构域的残基中。 Tam16先导分子获得的结合自由能值为-51.43 kcal/mol。当将此结果与其余类似物的 Delta G（结合）值进行比较时，发现药物 Tam16 排名最高：此结果与 Aggarwal 及其合作者获得的实验结果一致，其中验证了 Tam16 的 IC50 是抑制 Pks13 所需的最小（IC50 = 0.19 μM）。能量分解分析表明，与抑制剂相互作用最多的残基是：Ser1636、Tyr1637、Asn1640、Ala1667、Phe1670和Tyr1674，其中Phe1670的最大能量贡献尤其显着。对于先导分子 Tam16，与苯酚羟基的氢键在其他类似物中未观察到，从而产生了更稳定的分子结构。 Aggarwal 及其同事报告说，这种氢键决定了分子的稳定性，优化了其物理化学、毒理学和药代动力学特性。
In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the C alpha atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (Delta G(bind)) obtained for the Tam16 lead molecule was of -51.43 kcal/mol. When comparing this result with the Delta G(bind) values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC50 for Tam16 is the smallest necessary to inhibit the Pks13 (IC50 = 0.19 mu M). The energy decomposition analysis suggested that the residues which most interact with inhibitors are: Ser1636, Tyr1637, Asn1640, Ala1667, Phe1670, and Tyr1674, from which the greatest energy contribution to Phe1670 was particularly notable. For the lead molecule Tam16, a hydrogen bond with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure. Aggarwal and colleagues reported this hydrogen bonding as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.