Jawarkar Rahul D, Zaki Magdi E A, Al-Hussain Sami A, Al-Mutairi Aamal A, Samad Abdul, Masand Vijay, Humane Vivek, Mali Suraj, Alzahrani Abdullah Yahya Abdullah, Rashid Summya, Elossaily Gehan M
Department of Medicinal Chemistry and Drug discovery, Dr. Rajendra Gode Institute of Pharmacy, Amravati, Maharashtra, India.
Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia.
J Biomol Struct Dyn. 2024 Feb 22:1-31. doi: 10.1080/07391102.2024.2319104.
A lysine-specific demethylase is an enzyme that selectively eliminates methyl groups from lysine residues. KDM5A, also known as JARID1A or RBP2, belongs to the KDM5 Jumonji histone demethylase subfamily. To identify novel molecules that interact with the LSD5A receptor, we created a quantitative structure-activity relationship (QSAR) model. A group of 435 compounds was used in a study of the quantitative relationship between structure and activity to guess the IC50 values for blocking LASD5A. We used a genetic algorithm-multilinear regression-based quantitative structure-activity connection model to forecast the bioactivity (IC) of 1615 food and drug administration pharmaceuticals from the zinc database with the goal of repurposing clinically used medications. We used molecular docking, molecular dynamic simulation modelling, and molecular mechanics generalised surface area analysis to investigate the molecule's binding mechanism. A genetic algorithm and multi-linear regression method were used to make six variable-based quantitative structure-activity relationship models that worked well ( = 0.8521, = 0.8438, and = 0.8414). ZINC000000538621 was found to be a new hit against LSD5A after a quantitative structure-activity relationship-based virtual screening of 1615 zinc food and drug administration compounds. The docking analysis revealed that the hit molecule 11 in the KDM5A binding pocket adopted a conformation similar to the pdb-6bh1 ligand (docking score: -8.61 kcal/mol). The results from molecular docking and the quantitative structure-activity relationship were complementary and consistent. The most active lead molecule 11, which has shown encouraging results, has good absorption, distribution, metabolism, and excretion (ADME) properties, and its toxicity has been shown to be minimal. In addition, the MTT assay of ZINC000000538621 with MCF-7 cell lines backs up the in silico studies. We used molecular mechanics generalise borne surface area analysis and a 200-ns molecular dynamics simulation to find structural motifs for KDM5A enzyme interactions. Thus, our strategy will likely expand food and drug administration molecule repurposing research to find better anticancer drugs and therapies.
赖氨酸特异性去甲基化酶是一种能选择性地从赖氨酸残基上去除甲基的酶。KDM5A，也称为JARID1A或RBP2，属于KDM5 Jumonji组蛋白去甲基化酶亚家族。为了鉴定与LSD5A受体相互作用的新分子，我们创建了一个定量构效关系（QSAR）模型。一组435种化合物用于研究结构与活性之间的定量关系，以推测阻断LASD5A的IC50值。我们使用基于遗传算法-多元线性回归的定量构效关系模型，从锌数据库预测1615种美国食品药品监督管理局（FDA）药品的生物活性（IC），目的是重新利用临床使用的药物。我们使用分子对接、分子动力学模拟建模和分子力学广义表面积分析来研究该分子的结合机制。采用遗传算法和多元线性回归方法建立了六个基于变量的定量构效关系模型，效果良好（R² = 0.8521、Q² = 0.8438和Q²ext = 0.8414）。在对1615种FDA锌化合物进行基于定量构效关系的虚拟筛选后，发现ZINC000000538621是一种针对LSD5A的新的活性化合物。对接分析表明，命中分子11在KDM5A结合口袋中的构象与pdb-6bh1配体相似（对接分数：-8.61 kcal/mol）。分子对接和定量构效关系的结果相互补充且一致。活性最强的先导分子11已显示出令人鼓舞的结果，具有良好的吸收、分布、代谢和排泄（ADME）特性，并且其毒性已被证明极小。此外，ZINC000000538621对MCF-7细胞系的MTT试验支持了计算机模拟研究。我们使用分子力学广义Born表面积分析和200 ns的分子动力学模拟来寻找KDM5A酶相互作用的结构基序。因此，我们的策略可能会扩展FDA分子重新利用研究，以找到更好的抗癌药物和疗法。
