Ahmed Basharat, Khan Sara, Nouroz Faisal, Farooq Umar, Khalid Saba
Department of Bioinformatics, Hazara University, Mansehra, Pakistan.
Department of Chemistry, COMSATS University, Abbottabad, Pakistan.
J Biomol Struct Dyn. 2022;40(19):8825-8839. doi: 10.1080/07391102.2021.1918253. Epub 2021 Apr 30.
Cyclin-dependent kinases (CDKs) belong to a family of multifunctional enzymes that control cell cycle modifications, transcription, and cell proliferation. Their dysfunctions result in different diseases like cancer making them an important drug target in oncology and beyond. The present study aims at identifying the selective inhibitors for ATP binding site in CDK proteins (CDK1, CDK2, CDK4, and CDK5) following a multi-target drug designing approach. Significant challenges lie in identifying the selective inhibitor for the ATP binding site as this region is highly conserved in all protein kinases. Molecular docking coupled with molecular dynamics simulation and free energy of binding calculations (MMPBSA/MMGBSA) were used to identify the potent competitive ATP binding site inhibitors. All the four proteins were docked against the library of drug-like compounds and the outcomes of the docking study were further analyzed by Molecular dynamics (total of 6s) and MMPB/GBSA techniques. Five different inhibitors for structurally distant protein kinases, i.e. CDK1, CDK2, CDK4, and CDK5 are identified with the binding energy (Δ-PB) in the range -18.24 to -28.43Kcal/mol. Mechanistic complexities associated with the binding of the inhibitor are unraveled by carefully analyzing the MD trajectories. It is observed that certain residues (Lys33, Asp127, Asp145, Tyr15, Gly16, Asn144) and regions are critical for the retention of inhibitors in active pocket, and significant conformational changes take place in the active site region as well as its neighbor following the entry of the ligand inside active pocket as inferred by RMSD and RMSF. It is observed that LIG3 and LIG4 are the best possible inhibitors as reflected from their high binding energy, interaction pattern, and their retention inside the active pocket. This study will facilitate the process of multi-target drug designing against CDK proteins and can be used in the development of potential therapeutics against different diseases.
细胞周期蛋白依赖性激酶（CDKs）属于一类多功能酶，可控制细胞周期修饰、转录和细胞增殖。它们的功能失调会导致癌症等不同疾病，使其成为肿瘤学及其他领域重要的药物靶点。本研究旨在采用多靶点药物设计方法，鉴定CDK蛋白（CDK1、CDK2、CDK4和CDK5）中ATP结合位点的选择性抑制剂。识别ATP结合位点的选择性抑制剂存在重大挑战，因为该区域在所有蛋白激酶中高度保守。分子对接结合分子动力学模拟和结合自由能计算（MMPBSA/MMGBSA）用于鉴定有效的竞争性ATP结合位点抑制剂。所有这四种蛋白都与类药物化合物库进行对接，对接研究的结果通过分子动力学（共6秒）和MMPB/GBSA技术进一步分析。鉴定出五种针对结构上不同的蛋白激酶（即CDK1、CDK2、CDK4和CDK5）的不同抑制剂，其结合能（Δ-PB）在-18.24至-28.43千卡/摩尔范围内。通过仔细分析MD轨迹，揭示了与抑制剂结合相关的机制复杂性。观察到某些残基（Lys33、Asp127、Asp145、Tyr15、Gly16、Asn144）和区域对于抑制剂保留在活性口袋中至关重要，并且如RMSD和RMSF所推断，随着配体进入活性口袋后，活性位点区域及其相邻区域发生了显著的构象变化。观察到LIG3和LIG4是最佳的可能抑制剂，这从它们的高结合能、相互作用模式以及它们在活性口袋中的保留情况可以看出。本研究将促进针对CDK蛋白的多靶点药物设计过程，并可用于开发针对不同疾病的潜在疗法。
