Department of Bioengineering, Integral University, Lucknow, Uttar Pradesh, India.
Department of Biosciences, Integral University, Lucknow, India.
Cell Biochem Funct. 2022 Jul;40(5):451-472. doi: 10.1002/cbf.3707. Epub 2022 Jun 27.
The kinesin family member C1 (KIFC1) is an essential protein that facilitates the bipolar division of neoplastic cells. Inhibiting KIFC1 by small molecules is a lucrative strategy to impede bipolar mitosis leading to the apoptosis of cancerous cells. The research aims to envisage small-molecule inhibitors targeting KIFC1. The Mcule database, a comprehensive online digital platform containing more than five million chemical compounds, was used for structure-based virtual screening (SBVS). Druglikeness filtration sifted 2,293,282 chemical hits that further narrowed down to 49 molecules after toxicity profiling. Finally, 39 compounds that comply with the BOILED-Egg permeation predictive model of the ADME rules were carried forward for multiscoring docking using the AutoDock Vina inbuilt to Mcule drug discovery platform, DockThor and SwissDock tools. The mean of ΔG terms produced by docking tools was computed to find consensus top ligand hits. AZ82 exhibited stronger binding (Consensus ΔG: -7.99 kcal mol ) with KIFC1 among reference inhibitors, for example, CW069 (-7.57 kcal mol ) and SR31527 (-7.01 kcal mol ). Ten ligand hits namely, Mcule-4895338547 (Consensus ΔG: -8.69 kcal mol ), Mcule-7035674888 (-8.42 kcal mol ), Mcule-5531166845 (-8.53 kcal mol ), Mcule-3248415882 (-8.55 kcal mol ), Mcule-291881733 (-8.41 kcal mol ), Mcule-5918624394 (-8.44), Mcule-3470115427 (-8.47), Mcule-3686193135 (-8.18 kcal mol ), Mcule-3955355291 (8.09 kcal mol ) and Mcule-9534899193 (-8.01 kcal mol ) depicted strong binding interactions with KIFC1 in comparison to potential reference inhibitor AZ82. The top four ligands and AZ82 were considered for molecular dynamics simulation of 50 ns duration. Toxicity profiling, physicochemical properties, lipophilicity, solubility, pharmacokinetics, druglikeness, medicinal chemistry attributes, average potential energy, RMSD, RMSF, SASA, ΔGsolv and Rg analyses forecast the ligand mcule-4895338547 as a promising inhibitor of KIFC1.
驱动蛋白家族成员 C1（KIFC1）是一种必需的蛋白质，可促进肿瘤细胞的两极分裂。通过小分子抑制 KIFC1 是一种很有前途的策略，可以阻止两极有丝分裂，导致癌细胞凋亡。本研究旨在设想针对 KIFC1 的小分子抑制剂。Mcule 数据库是一个包含超过 500 万个化合物的全面在线数字平台，用于基于结构的虚拟筛选（SBVS）。药物相似性过滤筛选出 2293282 个化学命中，进一步缩小到毒性分析后 49 个分子。最后，符合 ADME 规则的 BOILED-Egg 渗透预测模型的 39 种化合物被推进到 Mcule 药物发现平台中的 AutoDock Vina 进行多评分对接，DockThor 和 SwissDock 工具。使用对接工具计算ΔG 项的平均值，以找到共识的顶级配体命中。在参考抑制剂中，AZ82 与 KIFC1 的结合更强（共识ΔG：-7.99 kcal/mol），例如 CW069（-7.57 kcal/mol）和 SR31527（-7.01 kcal/mol）。十个配体命中，即 Mcule-4895338547（共识ΔG：-8.69 kcal/mol）、Mcule-7035674888（-8.42 kcal/mol）、Mcule-5531166845（-8.53 kcal/mol）、Mcule-3248415882（-8.55 kcal/mol）、Mcule-291881733（-8.41 kcal/mol）、Mcule-5918624394（-8.44）、Mcule-3470115427（-8.47）、Mcule-3686193135（-8.18 kcal/mol）、Mcule-3955355291（8.09 kcal/mol）和 Mcule-9534899193（-8.01 kcal/mol）与 KIFC1 具有强烈的结合相互作用，与潜在的参考抑制剂 AZ82 相比。前四个配体和 AZ82 被考虑进行 50 ns 持续时间的分子动力学模拟。毒性分析、物理化学性质、亲脂性、溶解度、药代动力学、药物相似性、药物化学特性、平均势能、RMSD、RMSF、SASA、ΔGsolv 和 Rg 分析预测配体 mcule-4895338547 是 KIFC1 的一种很有前途的抑制剂。
