Design and study of in silico binding dynamics of certain isoxazole bearing leads against Aβ-42 and BACE-1 loop in protein fibrillation

Abstract

Aims: Design of isoxazole bearing leads as dual inhibitors against Amyloid β and BACE-1 loop in protein fibrillation Background: Protein fibrillation is one of the key reasons for several diseases namely Alzheimer’s, Parkinson’s, and many others. One of the key strategies of preventing protein fibrillation is destabilizing the protein fibrils themselves or inhibiting the amyloid fibril-forming pathway in the initial stage. Introduction: Attempts have been taken to design newer leads to inhibit protein fibrillation by targeting β-amyloidogenesis pathway in brain. Exploiting interfenestration between Amyloid β -42 protein and BACE-1 (β-site amyloid precursor protein cleaving enzyme) for amyloidogenesis, studies are undertaken to design dual inhibitor against the same. Method: In vitro binding interactions were found using docking, de novo ligand design, MD simulation study Results: Three compounds bearing isoxazole heterocyclic nucleus were designed which could successfully bind to the hydrophobic raft and salt bridge residues Asp 23-Lys-26 of Amyloid β destabilizing the growing fibril. Additionally, one of our candidate compounds exhibited force of interaction with Thr232 at S3 pocket of BACE-1, interacted with key residue Asp228, Tyr71, and Thr72 of the β-hairpin flap and hydrogen bonding with Gly11 at loop 10s. Conclusion: Protein flexibility dynamics of the Aβ-42 protein revealed that there is a considerable conformational change of the same with or without ligand binding. The lower RMSF of the bound region and reprogramming of residual contacts within the Aβ-42 protein suggested successful binding of the ligand with the protein lowering the access for further β-β dimerization.