Computational Simulations Identify Pyrrolidine-2,3-Dione Derivatives as Novel Inhibitors of Cdk5/p25 Complex to Attenuate Alzheimer’s Pathology

Abstract

Mechanistically, neurotoxic insults provoke Ca2+-mediated calpain activation, which cleaves the cytoplasmic region of membrane-embedded p35 and produces its truncated form p25. Upon physical interaction, cyclin-dependent kinase 5 (Cdk5) and p25 forms hyperactivated Cdk5/p25 complex and causes severe neuropathological aberrations including hyperphosphorylated tau-mediated neurofibrillary tangles formation, Alzheimer’s symptoms, and neuronal death. Therefore, the inhibition of Cdk5/p25 complex may relieve p-tau-mediated Alzheimer’s pathology. Herein, computational simulations have identified pyrrolidine-2,3-dione derivatives as novel inhibitors of Cdk5/p25 complex. A ligand-based pharmacophore was designed and employed as 3D query to retrieve drug-like molecules from chemical databases. By molecular docking, drug-like molecules obtaining dock score > 67.67 (Goldcore of the reference compound) were identified. Molecular dynamics simulation and binding free energy calculation retrieved four pyrrolidine-2,3-dione derivatives as novel candidate inhibitors of Cdk5/p25. The root means square deviation of Cdk5/p25 in complex with candidate inhibitors obtained an average value of ~2.15 Å during the 30 ns simulation period. Molecular interactions analysis suggested that each inhibitor occupied the ATP-binding site of Cdk5/p25 and formed stable interactions. Finally, the binding free energy estimation suggested that each inhibitor had lowest binding energy than the reference compound (−113.10 kJ/mol) to recapitulate their strong binding with Cdk5/p25. Overall, these inhibitors could mitigate tau-mediated Alzheimer’s phenotype.

Insilico drug repurposing using FDA approved drugs against Membrane protein of SARS-CoV-2

“…Based on the RMSD plots, last 10 ns simulation trajectories were selected and a total of 40 snapshots were taken at a regular interval. The g_mmpbsa tool for GROMACS was employed to calculate the different parameters of binding free energies with the methodologies described in previous reports [46][47][48][49] .…”

Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

“…Therefore, we argue that our pharmacophore model, generated with similar features as previous studies, gives reliable results for retrieving compounds that display a better binding affinity towards Hpse. The chosen Hpse pharmacophore model with the highest rank score was further validated by the decoy set validation method, generating a GF score of 0.72, which is near the ideal model range value of 1 ( Table 2 ) [ 53 , 54 , 55 ]. The validated model was, thus, considered to be robust for retrieving molecules from an external database, and therefore, the resultant model was allowed to screen the InterBioScreen database composed of natural (69,034) and synthetic (195,469) compounds ( Figure 1 ).…”

The role of Cdk5 in neurological disorders

“…Recent studies have found some new substrates and signaling pathways related to Cdk5 in AD, such asCdk5-Mcl-1axis (Nikhil and Shah, 2017 ), ALDH1A1 (Nikhil et al, 2019 ), miR-125b (Zhuang et al, 2020a ), and miR-504-3p (Chen et al, 2022 ). New Cdk5 inhibitors are also being studied in various AD models like pyrrolidine-2,3-dione, and TFP5 (Shukla et al, 2017 ; Zeb et al, 2019a , b ). It is also found that a traditional Chinese medicine, Nano-HO, improves cognitive function in AD by modulating the signaling pathway JNK/cdk5/GSK-3β (Qu et al, 2021 ).…”