Computational approaches for evaluation of isobavachin as potential inhibitor against t877a and w741l mutations in prostate cancer

Prostate cancer is the World’s second most common cancer, with the fifth-highest male mortality rate. Point mutations such as T877A and W741L are frequently seen in advanced prostate cancer patients, conferring drug-resistance and hence driving cancer growth. Such occurrence of drug resistance in prostate cancer necessitates designing of suitable ligands to ensure better interactions with the receptors which can block the progression of the disease. The present study focus on the modification of plant-derived flavonoids that might act as inhibitors against such point mutations namely, T877A and W741L. In T877A mutation threonine is substituted by alanine at the 877 codon and W741L mutation, tryptophan is substituted by lysine at the 741 codon in prostate cancer. The study revolved on the aspect of the evaluation of Isobavachin and its derivatives as a potential agent to tackle such point mutations by using the <i>in silico</i> approach. A total of 98 molecular dockings were performed to find the ligand-receptor complexes with the lowest binding energy employing Autodock Software to conduct the blind and site-specific docking. Additionally, ligands were screened for Drug-likeness and toxicity using several tools yielding eight possible drug candidates. Based on the results of Molecular Docking, Drug-likeness, and ADMET testing, ten structures, including six complexes and three receptors were subjected to molecular dynamics simulation of 100 ns covering RMSD, RMSF, Rg, and MM/PBSA. Based on the simulation results, Isobavachin, IsoMod4, and IsoMod7 were concluded to be stable and exhibited potential properties for developing a novel drug to combat prostate cancer and its associated drug-resistance. Communicated by Ramaswamy H. Sarma

前列腺癌是全球第二大常见癌症，男性死亡率位列第五。晚期前列腺癌患者中常出现T877A与W741L两类点突变，此类突变可诱导耐药性产生，进而推动癌症进展。针对前列腺癌的耐药性问题，亟需设计适配的配体以实现与受体的高效结合，阻断疾病进程。本研究聚焦于植物来源黄酮类化合物的修饰改造，这类化合物有望作为针对T877A和W741L点突变的抑制剂。具体而言，前列腺癌的T877A突变是指第877位密码子处的苏氨酸被丙氨酸取代，而W741L突变则是第741位密码子处的色氨酸被赖氨酸取代。本研究采用计算机辅助（in silico）方法，评估异补骨脂素（Isobavachin）及其衍生物作为应对此类点突变的潜在药物的潜力。研究共开展98次分子对接实验，使用Autodock软件进行盲对接与位点特异性对接，以筛选结合能最低的配体-受体复合物。此外，研究通过多款工具对配体进行类药性与毒性筛选，最终获得8种潜在候选药物。基于分子对接、类药性及ADMET（吸收-分布-代谢-排泄-毒性）测试结果，选取包含6种复合物与3种受体在内的共10种结构开展时长100纳秒的分子动力学模拟，分析维度涵盖均方根偏差（RMSD）、均方根波动（RMSF）、回旋半径（Rg）以及分子力学/泊松-玻尔兹曼表面积（MM/PBSA）。基于模拟结果，最终认定异补骨脂素、IsoMod4与IsoMod7稳定性优异，具备开发为新型药物以对抗前列腺癌及其相关耐药性的潜力。本文由Ramaswamy H. Sarma供稿。