Acylguanidine-BACE1 complex: Insights of intermolecular interactions and dynamics

Alzheimer disease (AD) is a harmful neurodegenerative disorder which arises mainly due to awful deposition of amyloid β (Aβ) peptide in the brain of AD patients. Aβ aggregates from the amyloid precursor protein (APP) by the sequential action of β-Secretase (Beta site APP Cleaving Enzyme, BACE1); hence, inhibition of BACE1 is the primary target for the treatment of AD. As per the experimental report, acylguanidine is a synthetic inhibitor of BACE1, it exhibits high binding affinity towards BACE1. In the present computational study, we aimed to understand the molecular binding mechanism of acylguanidine with BACE1 from the structure and conformation, intermolecular interactions, charge density and electrostatic properties, stability and binding free energy of acylguanidine molecule in the active site of BACE1. To investigate this, molecular docking, QM/MM based charge density analysis and MD simulation have been performed on acylguanidine with BACE1. Acylguanidine shows large binding affinity towards BACE1 and it gives strong hydrogen bonding and hydrophobic interactions with the active site amino acid residues of BACE1. In addition, QM/MM based charge density analysis of acylguanidine was carried out to understand its charge density distribution in the active site of BACE1. The conformational flexibility, charge density redistribution and the modification of electrostatic properties of acylguanidine in the active site have been compared to its corresponding gas phase structure. Further, the molecular dynamics simulation on acylguanidine-BACE1 was carried out, which gives the stability of acylguanidine in the active site of BACE1. The MM-GBSA free energy displays the binding affinity of the acylguanidine and further the decomposition energy reveals the validity of intermolecular interactions.