Computational Simulations Identified Two Candidate Inhibitors of Cdk5/p25 to Abrogate Tau-associated Neurological Disorders

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.

Computer-Aided Drug Design of β-Secretase, γ-Secretase and Anti-Tau Inhibitors for the Discovery of Novel Alzheimer’s Therapeutics

“…A group of marine indole alkaloids isolated from the marine tunicate Aplidium were identified as scaffolds for designing new anti-Tau hyperphosphorylation inhibitors using docking and MD simulations [149]. Docking calculation followed by MD simulations and binding free energy analysis led to the identification of novel anti-Tau hyperphosphorylation inhibitors of Cdk5 which occupied the ATP-binding site of the enzyme [150]. A set of pyrazolopyrimidine derivatives, which are inhibitors of GSK3β, were studied with docking calculations and 3D-QSAR to develop reliable predictive models for design new compounds to inhibit Tau hyperphosphorylation [151].…”

CDK5: Key Regulator of Apoptosis and Cell Survival

“…Unlike other CDKs that require the binding of cyclins in order for their activation, CDK5 requires the binding of p35, p39, or p25 (a proteolytic fragment of p35) for activation. p35 (NCK5a, neuronal CDK5 activator) was first discovered due to its association and activation of CDK5 [17][18][19]. However, p39 (NCK5ai, neuronal CDK5 activator isoform) was first identified as a 39 kDa isoform of p35 that shared 57% amino acid homology with p35 [20], p25 was first discovered as a truncated form of p35 that was found in the neurons of Alzheimer patients [21], and subsequent studies identified that cleavage of p35 into p25 was calpain-and dephosphorylation-dependent [22][23][24].…”

“…The proteolytic p25 fragment of p35 exhibits a different subcellular localization with and is more stable that its precursor p35. CDK5/p25 have shown to phosphorylate both Tau and MAP1B found in neurofibrillary tangles (NFTs) compared with CDK5/p35 [19,31]. CDK5 has been shown to have various roles in synapse formation, maintenance, and synaptic communication.…”

Discovery of a Novel Natural Allosteric Inhibitor That Targets NDM-1 Against Escherichia coli

“…The system was simulated for 100 ns using the Amber 99sb force field ( Sakkiah et al, 2018 ) and the TIP3P water model ( Lim et al, 2019 ). The free binding energy between NDM-1 and the ligand was calculated by the Molecular Mechanics/Generalized Born Surface Area (MM-GBSA) method ( Liu et al, 2018b ; Zeb et al, 2019 ; Nie et al, 2020 ).…”