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.
Keywords: 2D, Two-dimentional; 3D, Three-dimentional; AD, Alzheimer's disease; ADMET, Absorption, distribution, metabolism, excretion, and toxicity; ASP, Astex statistical potential; Aβ, Amyloid beta; BBB, Blood-brain barrier; CGMC, Cyclin-dependent kinases, mitogen-activated protein kinases, glycogen synthase kinases, and Cdk-like kinases; Cdk5, Cyclin-dependent kinase 5; Cdk5/p25 inhibitors; Cdks, Cyclin-dependent kinases; DS, Discovery Studio; EF, Enrichment factor; GA, Genetic algorithm; GFA, Genetic Function Approximation; GH, Guner-Henry; GOLD, Genetic optimization of ligand docking; GROMACS, Groningen Machine for Chemical Simulation; H-bond, Hydrogen bond; HBA, Hydrogen bond acceptor; HBD, Hydrogen bond donor; HD, Hungtington's disease; HYP, Hydrophobic; IBS, InterBioScreen; K, kelvin; MD, Molecular dynamics; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Molecular docking; Molecular dynamics simulation; NPT, Number particle, pressure, and temperature; NVT, Number of particles, volume, and temperature; P5, A 24-residues mimetic peptide of p35; PD, Parkinson's disease; PDB, Protein databank; PLP, Piecewise linear potential; PME, Particle mesh ewald; RMSD, Root mean square deviation; ROF, Rule of five; Structure-based pharmacophore modeling; TAT, Twin-arginine targeting; TIP3P, Transferable intermolecular potential with 3 points; Tau-pathogenesis; ZNPD, Zinc Natural Product Database.