Programme

P.103 -- Posters, VCTP-50

Date: Thursday, 7 August 2025

Time: 08:30 - 10:00

Tripeptides inhibit dual targets AChE and BACE-1: a computational study

Anh Tuan Do, ab Trung Hai Nguyen,ab Minh Quan Pham, cd Huy Truong Nguyen,b Nguyen Phuoc Long,e Van Van Vu,f Huong Thi Thu Phung *f and Son Tung Ngo*ab

a Laboratory of Biophysics, Institute for Advanced Study in Technology, Ton Duc Thang University, Ho Chi Minh City, Vietnam b Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City, Vietnam cInstitute of Chemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam d Graduate University of Science and Technology, Vietnam Academy of Science and Technology, Hanoi, Vietnam e Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea f NTT Hi-Tech Institute, Nguyen Tat Thanh University, Ho Chi Minh City, Vietnam

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with amyloid-beta (Aβ) plaques and acetylcholine deficits being central pathological features. Inhibition of dual targets including acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) represents a promising strategy to address cholinergic deficits and amyloid pathology. In this study, we used computational approaches to evaluate 8000 tripeptides as potential dual inhibitors of AChE and BACE-1. Machine learning models revealed the four top-lead tripeptides including WHM, HMW, WMH, and HWM. Molecular docking simulations indicated that WHM possessed the most favorable interactions through hydrogen bonds, π–π stacking, and salt bridges with key catalytic residues in both enzymes. Molecular dynamics simulations confirmed the stability of the protein–ligand complexes, with WHM exhibiting the most consistent conformations and significant disruption of catalytic residue geometries. Free energy perturbation analysis further supported WHM's superior stability across both targets. ADMET predictions suggested moderate oral absorption and limited brain penetration, consistent with the typical behavior of peptide-based compounds. Overall, WHM demonstrated the strongest potential as a dual inhibitor of AChE and BACE-1, offering a promising lead for future therapeutic development in AD.

Presenter: Do Anh Tuan