期刊名称：Computational and Structural Biotechnology Journal
印刷版ISSN：2001-0370
出版年度：2019
卷号：17
页码：579-590
DOI：10.1016/j.csbj.2019.04.010
出版社：Computational and Structural Biotechnology Journal
摘要：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.
关键词：Cdk5/p25 inhibitors ; Structure-based pharmacophore modeling ; Tau-pathogenesis ; Molecular docking ; Molecular dynamics simulation ; Cdk5 Cyclin-dependent kinase 5 ; Cdks Cyclin-dependent kinases ; CGMC Cyclin-dependent kinases; mitogen-activated protein kinases; glycogen synthase kinases; and Cdk-like kinases ; AD Alzheimer's disease ; PD Parkinson's disease ; HD Hungtington's disease ; MPTP 1-methyl-4-phenyl-1;2;3;6-tetrahydropyridine ; P5 A 24-residues mimetic peptide of p35 ; TAT Twin-arginine targeting ; Aβ Amyloid beta ; ZNPD Zinc Natural Product Database ; IBS InterBioScreen ; DS Discovery Studio ; GH Guner-Henry ; EF Enrichment factor ; ROF Rule of five ; ADMET Absorption; distribution; metabolism; excretion; and toxicity ; BBB Blood-brain barrier ; GOLD Genetic optimization of ligand docking ; PLP Piecewise linear potential ; ASP Astex statistical potential ; MD Molecular dynamics ; PME Particle mesh ewald ; K kelvin ; TIP3P Transferable intermolecular potential with 3 points ; GROMACS Groningen Machine for Chemical Simulation ; NVT Number of particles; volume; and temperature ; NPT Number particle; pressure; and temperature ; PDB Protein databank ; H-bond Hydrogen bond ; HBA Hydrogen bond acceptor ; HBD Hydrogen bond donor ; HYP Hydrophobic ; RMSD Root mean square deviation ; 2D Two-dimentional ; 3D Three-dimentional ; GA Genetic algorithm ; GFA Genetic Function Approximation
