Molecular Insights into the Interaction of a Small Molecule Inhibitor with Β- Secretase (Bace1) Enzyme: A Molecular Dynamics Simulation Study

Abstract

AD is a neurodegenerative, irreversible and progressive diseases. It is the most common cause of dementia affecting over 40 million people worldwide, but still there is no proper cure for this disease till now. According to World Alzheimer’s report 2018 the rate of AD enhanced by three times approximately by 2050.One of the major characteristics and chronic marks of AD is shown by the senile plaques and neurofibrillary tangles. These plaques and tangles affect the activity of brain or kills brain cells. Aβ peptides was derived from amyloid precursor protein (APP)by the cleavage of β-secretase (BACE-1), γ-secretaseenzymes and BACE-1 participates in the rate-limiting step in Aβ production. Thus BACE1 is an important target for the development of anti-Alzheimer’s agents along with Aβ peptide. In present study reported inhibitor PF-06751979 (C1) was selected to get insight into the inhibitory mechanism against BACE-1 using in silico studies. Results of the study, shows significant reduction in the fluctuation in loop regions i.e. insert–A (Phe159-Leu167), insert–B (Lys218-Asn221), insert–C (Ala251-Pro258), insert–D (Trp270-Gly273), insert–E (Glu290-Ser295) and insert–F (Gln316-Asp318) as compare to apo–BACE1. Interactions results also shoe the interactions with the active pocket residues of BACE-1 i.e. S1 (Gln73 and Phe108), S1´ (Thr72), S2 (Asn233), S3 (Ile110) and S4 (Gln73 and Thr232). Results also shows the interactions with flap residues (Gly66-Glu77) which confirms the strong binding with flap and keep the flap in close confirmation in the presence of C1.The molecular insights from the present study will help in the rational design of more potent drug molecules against AD.