Division of Applied Life Science, (BK21 Four), Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), 501 Jinju-Daero, Jinju, 52828, Republic of Korea.
Department of Bio & Medical Big Data (BK4 Program), Division of Life Sciences, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), 501 Jinju-Daero, Jinju, 52828, Republic of Korea.
J Mol Model. 2024 Jul 16;30(8):267. doi: 10.1007/s00894-024-06067-z.
Cyclin-dependent kinase 9 (CDK9) plays a significant role in gene regulation and RNA polymerase II transcription under basal and stimulated conditions. The upregulation of transcriptional homeostasis by CDK9 leads to various malignant tumors and therefore acts as a valuable drug target in addressing cancer incidences. Ongoing drug development endeavors targeting CDK9 have yielded numerous clinical candidate molecules currently undergoing investigation as potential CDK9 modulators, though none have yet received Food and Drug Administration (FDA) approval.
In this study, we employ in silico approaches including the molecular docking and molecular dynamics simulations for the virtual screening over the natural compounds library to identify novel promising selective CDK9 inhibitors. The compounds derived from the initial virtual screening were subsequently employed for molecular dynamics simulations and binding free energy calculations to study the compound's stability under virtual physiological conditions. The first-generation CDK inhibitor Flavopiridol was used as a reference to compare with our novel hit compound as a CDK9 antagonist. The 500-ns molecular dynamics simulation and binding free energy calculation showed that two natural compounds showed better binding affinity and interaction mode with CDK9 receptors over the reference Flavopiridol. They also showed reasonable figures in the predicted absorption, distribution, metabolism, excretion, and toxicity (ADMET) calculations as well as in computational cytotoxicity predictions. Therefore, we anticipate that the proposed scaffolds could contribute to developing potential and selective CDK9 inhibitors subjected to further validations.
细胞周期蛋白依赖性激酶 9（CDK9）在基础和刺激条件下在基因调控和 RNA 聚合酶 II 转录中发挥重要作用。CDK9 对转录动态平衡的上调导致各种恶性肿瘤，因此作为解决癌症发病率的有价值的药物靶点。目前正在针对 CDK9 的药物开发努力产生了许多临床候选分子，目前正在作为潜在的 CDK9 调节剂进行研究，尽管尚未获得美国食品和药物管理局（FDA）的批准。
在这项研究中，我们采用了包括分子对接和分子动力学模拟在内的计算方法，对天然化合物库进行虚拟筛选，以鉴定新型有前途的选择性 CDK9 抑制剂。从初始虚拟筛选中获得的化合物随后用于分子动力学模拟和结合自由能计算，以研究化合物在虚拟生理条件下的稳定性。第一代 CDK 抑制剂 Flavopiridol 被用作参考，与我们的新型命中化合物作为 CDK9 拮抗剂进行比较。500-ns 分子动力学模拟和结合自由能计算表明，两种天然化合物与 CDK9 受体的结合亲和力和相互作用模式优于参考 Flavopiridol。它们在预测的吸收、分布、代谢、排泄和毒性（ADMET）计算以及计算细胞毒性预测中也表现出合理的数值。因此，我们预计所提出的支架可以为进一步验证开发有潜力和选择性的 CDK9 抑制剂做出贡献。
