Development of Novel Isoxazole Bearing Lead against Alzheimer's disease By Docking Guided Virtual Screening and De Novo Ligand Design

Abnormal amyloid β protein (Aβ) aggregation is the initiating process of Alzheimer’s disease. Anti-amyloid compounds must inhibit such accumulation by stabilizing soluble Aβ oligomers by forming hydrogen bonds and π-π stacking. Recent reports suggest that curcumin inhibits Aβ fibril by producing structural changes in the salt bridge of Aβ protein and modifying fibril conformation. Curcumin analogs with pyrazole, isothiazole and isooxazoles exhibit considerable binding affinity comparable to that of curcumin. Multiple group replacement by various isosteres in curcumin gave significant results. In silico docking studies of compound (28) with both Aβ protein and β-secretase enzyme (BACE1) was found to be higher than that of standard. De novo ligand design generated best suitable derivative of the selected lead by iterations. Both compound (28) and de novo designed lead offspring reached the binding pocket of both the proteins, passed Lipinski’s rule of five and in silico toxicity testing by admetSAR.

Author(s): Souvik Basak*1, Puja Mishraa1 and Arup Mukherjee

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