Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis
Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis
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DOI：
10.3390/molecules25040904
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发表时间：
2020-02-02
期刊：
影响因子：
4.6
通讯作者：
Bishop, Ozlem Tastan
中科院分区：
文献类型：
--
作者：
Amusengeri, Arnold;Tata, Rolland Bantar;Bishop, Ozlem Tastan
在这个精准医学的时代，深入了解药物的耐药机制对于开发有效的治疗方法是不可或缺的。在这里，我们试图了解疟疾寄生虫酶二氢叶酸还原酶（DHFR）活性位点内的四个点突变（N51 I，C59 R，S108 N和I164 L）对抗疟药物乙胺嘧啶的耐药性的贡献。同源性建模用于获得野生型（WT）和突变体DHFR的全长模型。采用分子对接将乙胺嘧啶对接到生成的结构上。随后的全原子分子动力学（MD）模拟和结合自由能计算强调，乙胺嘧啶的稳定性和亲和力与其结合位点内的突变数量成反比，因此，耐药性的严重程度。一般来说，突变导致乙胺嘧啶的结合亲和力降低和DHFR的构象可塑性增加。接下来，应用动态残基网络分析（DRN）来确定突变和乙胺嘧啶结合对DHFR残基的通信处置的影响。DRN揭示了具有独特通讯特征的残基，区分了WT与耐药突变体以及结合乙胺嘧啶与不含乙胺嘧啶的模型。我们的研究结果提供了一个新的角度对突变诱导的耐药性的理解。
In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine's stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity. Generally, mutations led to reduced binding affinity to pyrimethamine and increased conformational plasticity of DHFR. Next, dynamic residue network analysis (DRN) was applied to determine the impact of mutations and pyrimethamine binding on communication dispositions of DHFR residues. DRN revealed residues with distinctive communication profiles, distinguishing WT from drug-resistant mutants as well as pyrimethamine-bound from pyrimethamine-free models. Our results provide a new perspective on the understanding of mutation-induced drug resistance.