Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
Department of Physics, Carl von Ossietzky University, Carl-von-Ossietzky-Strasse 9-11, 26129 Oldenburg, Germany.
J Chem Inf Model. 2021 Mar 22;61(3):1334-1345. doi: 10.1021/acs.jcim.0c01148. Epub 2021 Feb 22.
() is the main parasite known to cause malaria in humans. The antimalarial drug atovaquone is known to inhibit the Q-site of the cytochrome bc complex of , which ultimately blocks ATP synthesis, leading to cell death. Through the years, mutations of the cytochrome bc complex, causing resistance to atovaquone, have emerged. The present investigation applies molecular dynamics (MD) simulations to study how the specific mutations Y279S and L282V, known to cause atovaquone resistance in malarial parasites, affect the inhibition mechanism of two known inhibitors. Binding free energy estimates were obtained through free energy perturbation calculations but were unable to confidently resolve the effects of mutations due to the great complexity of the binding environment. Meanwhile, basic mechanistic considerations from the MD simulations provide a detailed characterization of inhibitor binding modes and indicate that the Y279S mutation weakens the natural binding of the inhibitors, while no conclusive effect of the L282V mutation could be observed.
疟原虫是已知导致人类疟疾的主要寄生虫。抗疟药物阿托伐醌已知可抑制疟原虫细胞色素 bc 复合物的 Q 位，从而阻止 ATP 合成，导致细胞死亡。多年来，疟原虫细胞色素 bc 复合物的突变导致对阿托伐醌的耐药性已经出现。本研究应用分子动力学 (MD) 模拟来研究已知导致疟原虫抗药性的 Y279S 和 L282V 两种突变如何影响两种已知抑制剂的抑制机制。通过自由能微扰计算获得了结合自由能估计值，但由于结合环境非常复杂，无法确定突变的影响。同时，MD 模拟的基本力学考虑提供了抑制剂结合模式的详细特征描述，并表明 Y279S 突变削弱了抑制剂的天然结合，而 L282V 突变则没有观察到明显的影响。
