Zeb Amir, Son Minky, Yoon Sanghwa, Kim Ju Hyun, Park Seok Ju, Lee Keun Woo
Division of Life Science, Division of Applied Life Sciences (BK21 Plus), Research Institute of Natural Sciences (RINS), Gyeongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Gyeongnam, Republic of Korea.
Department of Chemistry (BK21 Plus), Research Institute of Natural Science (RINS), Geyongsang National University (GNU), 501 Jinju-daero, Jinju 52828, Gyeongnam, Republic of Korea.
Comput Struct Biotechnol J. 2019 Apr 22;17:579-590. doi: 10.1016/j.csbj.2019.04.010. eCollection 2019.
Deregulation of Cdk5 is a hallmark in neurodegenerative diseases and its complex with p25 forms Cdk5/p25, thereby causes severe neuropathological insults. Cdk5/p25 abnormally phosphorylates tau protein, and induces tau-associated neurofibrillary tangles in neurological disorders. Therefore, the pharmacological inhibition of Cdk5/p25 alleviates tau-associated neurological disorders. Herein, computational simulations probed two candidate inhibitors of Cdk5/p25. Structure-based pharmacophore investigated the essential complementary chemical features of ATP-binding site of Cdk5 in complex with roscovitine. Resultant pharmacophore harbored polar interactions with Cys83 and Asp86 residues and non-polar interactions with Ile10, Phe80, and Lys133 residues of Cdk5. The chemical space of selected pharmacophore was comprised of two hydrogen bond donors, one hydrogen bond acceptor, and three hydrophobic features. Decoy test validation of pharmacophore obtained highest Guner-Henry score (0.88) and enrichment factor score (7.23). The screening of natural product drug-like databases by validated pharmacophore retrieved 1126 compounds as candidate inhibitors of Cdk5/p25. The docking of candidate inhibitors filtered 10 molecules with docking score >80.00 and established polar and non-polar interactions with the ATP-binding site residues of Cdk5/p25. Finally, molecular dynamics simulation and binding free energy analyses identified two candidate inhibitors of Cdk5/p25. During 30 ns simulation, the candidate inhibitors established <3.0 Å root mean square deviation and stable hydrogen bond interactions with the ATP-binding site residues of Cdk5/p25. The final candidate inhibitors obtained lowest binding free energies of -122.18 kJ/mol and - 117.26 kJ/mol with Cdk5/p25. Overall, we recommend two natural product candidate inhibitors to target the pharmacological inhibition of Cdk5/p25 in tau-associated neurological disorders.
细胞周期蛋白依赖性激酶5（Cdk5）的失调是神经退行性疾病的一个标志，它与p25形成复合物Cdk5/p25，从而导致严重的神经病理损伤。Cdk5/p25异常磷酸化tau蛋白，并在神经疾病中诱导tau相关的神经原纤维缠结。因此，对Cdk5/p25的药理学抑制可减轻tau相关的神经疾病。在此，通过计算模拟探究了两种Cdk5/p25候选抑制剂。基于结构的药效团研究了Cdk5与roscovitine复合物中ATP结合位点的基本互补化学特征。所得药效团与Cdk5的Cys83和Asp86残基存在极性相互作用，与Ile10、Phe80和Lys133残基存在非极性相互作用。所选药效团的化学空间由两个氢键供体、一个氢键受体和三个疏水特征组成。药效团的诱饵测试验证获得了最高的Guner-Henry评分（0.88）和富集因子评分（7.23）。通过经过验证的药效团对天然产物类药物数据库进行筛选，检索到1126种化合物作为Cdk5/p25的候选抑制剂。候选抑制剂的对接筛选出10个对接分数>80.00的分子，并与Cdk5/p25的ATP结合位点残基建立了极性和非极性相互作用。最后，分子动力学模拟和结合自由能分析确定了两种Cdk5/p25候选抑制剂。在30纳秒的模拟过程中，候选抑制剂与Cdk5/p25的ATP结合位点残基的均方根偏差<3.0埃，并建立了稳定的氢键相互作用。最终的候选抑制剂与Cdk5/p25的结合自由能最低，分别为-122.18 kJ/mol和-117.26 kJ/mol。总体而言，我们推荐两种天然产物候选抑制剂用于tau相关神经疾病中Cdk5/p25的药理学抑制。
