College of Pharmacy and Biological Engineering, Sichuan Industrial Institute of Antibiotics, Key Laboratory of Medicinal and Edible Plants Resources Development of Sichuan Education Department, Chengdu University, Chengdu, 610106, China.
Phys Chem Chem Phys. 2019 Aug 21;21(33):18105-18118. doi: 10.1039/c9cp02645b.
With the emergence of drug-resistant Plasmodium falciparum, the treatment of malaria has become a significant challenge; therefore, the development of antimalarial drugs acting on new targets is extremely urgent. In Plasmodium falciparum, type II nicotinamide adenine dinucleotide (NADH) dehydrogenase (NDH-2) is responsible for catalyzing the transfer of two electrons from NADH to flavin adenine dinucleotide (FAD), which in turn transfers the electrons to coenzyme Q (CoQ). As an entry enzyme for oxidative phosphorylation, NDH-2 has become one of the popular targets for the development of new antimalarial drugs. In this study, reliable motion trajectories of the NDH-2 complex with its co-factors (NADH and FAD) and inhibitor, RYL-552, were obtained by comparative molecular dynamics simulations. The influence of cofactor binding on the global motion of NDH-2 was explored through conformational clustering, principal component analysis and free energy landscape. The molecular interactions of NDH-2 before and after its binding with the inhibitor RYL-552 were analyzed, and the key residues and important hydrogen bonds were also determined. The results show that the association of RYL-552 results in the weakening of intramolecular hydrogen bonds and large allosterism of NDH-2. There was a significant positive correlation between the angular change of the key pocket residues in the NADH-FAD-pockets that represents the global functional motion and the change in distance between NADH-C4 and FAD-N5 that represents the electron transfer efficiency. Finally, the possible non-competitive inhibitory mechanism of RYL-552 was proposed. Specifically, the association of inhibitors with NDH-2 significantly affects the global motion mode of NDH-2, leading to widening of the distance between NADH and FAD through cooperative motion induction; this reduces the electron transfer efficiency of the mitochondrial respiratory chain. The simulation results provide useful theoretical guidance for subsequent antimalarial drug design based on the NDH-2 structure and the respiratory chain electron transfer mechanism.
随着耐青蒿素疟原虫的出现，疟疾的治疗已成为一个重大挑战；因此，开发针对新靶点的抗疟药物变得极为紧迫。在恶性疟原虫中，Ⅱ型烟酰胺腺嘌呤二核苷酸（NADH）脱氢酶（NDH-2）负责催化将两个电子从 NADH 转移到黄素腺嘌呤二核苷酸（FAD），FAD 再将电子转移到辅酶 Q（CoQ）。作为氧化磷酸化的入口酶，NDH-2 已成为开发新抗疟药物的热门靶点之一。在本研究中，通过比较分子动力学模拟获得了 NDH-2 与其辅因子（NADH 和 FAD）和抑制剂 RYL-552 的复合物的可靠运动轨迹。通过构象聚类、主成分分析和自由能景观探讨了辅因子结合对 NDH-2 整体运动的影响。分析了 NDH-2 与抑制剂 RYL-552 结合前后的分子相互作用，并确定了关键残基和重要氢键。结果表明，RYL-552 的结合导致 NDH-2 内部氢键减弱和大范围变构。代表全局功能运动的 NADH-FAD 口袋中关键口袋残基的角度变化与代表电子传递效率的 NADH-C4 和 FAD-N5 之间距离的变化之间存在显著正相关。最后，提出了 RYL-552 可能的非竞争性抑制机制。具体来说，抑制剂与 NDH-2 的结合会显著影响 NDH-2 的整体运动模式，通过协同运动诱导导致 NADH 和 FAD 之间的距离变宽；这会降低线粒体呼吸链的电子传递效率。模拟结果为基于 NDH-2 结构和呼吸链电子传递机制的后续抗疟药物设计提供了有用的理论指导。
