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Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological
Amir Zeb1, Minky Son1, Sanghwa Yoon1
1Division 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.
Abstract:
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.
Insights
Deregulation of Cyclin-dependent kinase 5 (Cdk5) is implicated in neurodegenerative diseases. This study identifies two natural compounds as potential inhibitors of the Cdk5/p25 complex, offering a new therapeutic strategy for tau-associated neurological disorders.
Area of Science:
- Biochemistry
- Neuroscience
- Computational Chemistry
Background:
- Cyclin-dependent kinase 5 (Cdk5) deregulation and its complex with p25 (Cdk5/p25) are key factors in neurodegenerative diseases.
- Cdk5/p25 abnormally phosphorylates tau protein, leading to neurofibrillary tangles and neuropathological damage.
Purpose of the Study:
- To identify novel pharmacological inhibitors of the Cdk5/p25 complex.
- To explore natural products as potential therapeutic agents for tau-associated neurological disorders.
Main Methods:
- Structure-based pharmacophore modeling of the Cdk5 ATP-binding site.
- Screening of natural product databases and molecular docking.
- Molecular dynamics simulations and binding free energy calculations.
Main Results:
- A validated pharmacophore model identified key interactions with Cdk5 residues (Cys83, Asp86, Ile10, Phe80, Lys133).
- Screening yielded 1126 candidate inhibitors, with 10 selected based on docking scores.
- Two natural product inhibitors demonstrated stable interactions and low binding free energies (-122.18 and -117.26 kJ/mol).
Conclusions:
- Two natural compounds effectively inhibit the Cdk5/p25 complex.
- These compounds show promise for the pharmacological treatment of tau-associated neurological disorders.
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