Development of Pyrazole Harbouring Novel Leads Against β-Amyloid Protein Fibrillation by in silico Drug Design.

Amyloid β (A β) peptide monomers polymerize to form insoluble amyloid fibril aggregates and accumulate as senile plaques which eventually leads to cognitive impairment. Modulating abnormal amyloid aggregation can be considered a therapeutic target for Alzheimer's disease. Recent studies support that Curcumin interferes with larger protein aggregate formation by destabilizing the salt bridge (Asp 23-Lys 28) of A β protein. The chemical library of curcumin derivative with pyrazole, isoxazole, and isothiazole showed considerable binding affinity comparable to that of curcumin. In silico docking studies of the library of the compound, revealed strong binding affinity with A β protein and β -secretase enzyme (BACE1). De novo ligand design coupled with manual pharmacophore mapping of our best-fitting lead revealed another ligand having a potential binding affinity with both A β protein and BACE-1. Both the compounds passed Lipinski's Rule of Five, in silico toxicity testing by admetSAR, and pharmacophore overlaps with Verubecestat, a compound under clinical trial against Alzheimer's disease. MD dynamic simulation study revealed the stability of protein after it binds to our ligand. Secondary structure determination was also done to observe the changes in α and β sheets of the protein with and without ligand binding. Ligand-based drug design was also carried out via pharmacophore mapping and searching the molecules via zinc database. Pyrazole bearing lead has been identified which may act as dual inhibitor of Amyloid β-42 protein and beta secretase enzyme responsible for protein fibrillation. The best ligand (compound 49) with highest docking scores, appropriate drug likeliness and less toxicity was selected as our lead compound and molecular dynamic simulation studies proved the stability of the compound in the α-β transitions of protein. DSSP plots also exhibited that the winner molecule hindered α-helix to β-sheet transition for many residues (seeding zone of β-β dimerization) in the binding pocket. [ABSTRACT FROM AUTHOR]