Structure-based identification of potent modulators from Centella asiatica targeting BACE-1

<h2>Abstract</h2> β-secretase enzyme 1 or BACE-1 is attributed to generating Aβ plaques, a key pathological feature of Alzheimer's disease (AD)-associated dementia, and is an attractive target for AD management. Due to acute side effects and toxicity, some potential candidate drugs failed in the clinical trial phase II/III, thus the development of new potential BACE-1 inhibitors with significant efficacy and safety profiles is the primary concern. <i>Centella Asiatica</i> (CA), a widely recognized medicinal plant, has gained attention for its significant cognitive benefits. Therefore, the present study aimed to identify the potent modulators from CA-derived compounds and characterize their binding in the active site of BACE-1 at a microsecond-level molecular simulation. Typically, 165 compounds of CA are collected using the IMPPAT database and literature review, which are subjected to ADME profiling to check blood-brain barrier (BBB) permeation capability. ADME prediction revealed that approximately 64.84 % of the compounds exhibited drug-like properties and crossed the blood-brain barrier. Afterwards, multistep molecular docking was used to screen out final potential candidates, where myricetin, quercetin, and vedelianin demonstrated significant docking and MM-GBSA scores. Further, the stability of the selected compounds was verified by a microsecond timescale molecular dynamics (MD) simulation and post-MM-GBSA calculation. However, MD simulation, post-MM-GBSA score, PCA, and DCCM analysis preferred the highest binding stability of vedelianin in the BACE-1 binding site with minimal structural changes. Besides, myricetin and quercetin also remained stable in the active pocket of BACE-1 interacting with key residues. Taken together, this in silico study focused on investigating the binding mood of CA-derived compounds and concluded that vedelianin, myricetin and quercetin of CA may bind and modulate BACE-1 activity with less conformational changes. In summary, CA-derived selected candidates could be potential against BACE-1, which could be a new therapeutic strategy for treating AD. This study may also facilitate the development of new novel analogues of these compounds with enhanced specificity and potency against BACE-1.