Structural and Energetic Affinity of Annocatacin B with ND1 Subunit of the Human Mitochondrial Respiratory Complex I as a Potential Inhibitor: An in silico Comparison Study with the Known Inhibitor Rotenone

ND1 subunit possesses the majority of the inhibitor binding domain of the human mitochondrial respiratory complex I (MRC-I). This is an attractive target for the search for new inhibitors that seek mitochondrial dysfunction. It is known, from in vitro experiments, some metabolites from Annona muricata called acetogenins have important biological activities such as anticancer, antiparasitic, and insecticide. Previous studies propose an inhibitory activity of bovine MRC-I by bis-tetrahydrofurans acetogenins such as annocatacin B, however, there are few studies on its inhibitory effect on human MRC-I. In this work, we evaluate in silico molecular and energetic affinity of the annocatacin B molecule with the human ND1 subunit in order to elucidate its potential capacity to be a good inhibitor of this subunit. For this purpose, quantum mechanical optimizations, molecular dynamics simulations and the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) analysis were performed. As a control to compare our outcomes, the molecule rotenone, which is a known MRC-I inhibitor, was chosen. Our results show that annocatacin B has a greater affinity for the ND1 structure, its size and folding were probably the main characteristics that contributed to stabilize the molecular complex. Furthermore, the MM/PBSA calculations showed a 35% stronger binding free energy compared to the rotenone complex. Detailed analysis of the binding free energy shows that the aliphatic chains of annocatacin B play a key role in molecular coupling by distributing favorable interactions throughout the major part of the ND1 structure. These results are consistent with experimental studies that mention that acetogenins may be good inhibitors of the MRC-I.

ND1亚基包含人类线粒体呼吸复合物I（mitochondrial respiratory complex I, MRC-I）的绝大多数抑制剂结合结构域，是筛选可诱发线粒体功能障碍的新型抑制剂的极具吸引力的靶点。已有体外实验证实，刺果番荔枝（Annona muricata）来源的一类名为番荔枝内酯（acetogenins）的代谢物，具备抗癌、抗寄生虫、杀虫等重要生物活性。既往研究表明，双四氢呋喃类番荔枝内酯（bis-tetrahydrofurans acetogenins）如安诺卡辛B（annocatacin B）可抑制牛源MRC-I，但针对其对人类MRC-I抑制作用的相关研究仍较为匮乏。本研究通过计算机模拟（in silico）方法，评估安诺卡辛B与人类ND1亚基的分子亲和性与能量结合特性，以阐明其作为该亚基优良抑制剂的潜在能力。为此，本研究开展了量子力学优化、分子动力学模拟以及分子力学/泊松-玻恩表面积（Molecular Mechanics/Poisson-Boltzmann Surface Area, MM/PBSA）分析。为对照验证实验结果，我们选用了已知的MRC-I抑制剂鱼藤酮（rotenone）作为对照分子。研究结果显示，安诺卡辛B与ND1结构具有更高的结合亲和性，其分子尺寸与折叠方式或许是促成该分子复合物稳定的主要特征。此外，MM/PBSA计算结果表明，其结合自由能较鱼藤酮复合物高出35%。对结合自由能的详细分析显示，安诺卡辛B的脂肪链通过在ND1结构的大部分区域分布有利相互作用，在分子对接过程中发挥关键作用。上述结果与已有实验研究结论相符，即番荔枝内酯或可成为MRC-I的优良抑制剂。