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

Area of Science:

• Computational chemistry
• Neuroscience
• Drug discovery

Background:

• Alzheimer's disease (AD) involves cognitive decline, amyloid plaques, and acetylcholine deficits.
• Dual inhibition of acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) is a key therapeutic strategy for AD.

Purpose of the Study:

• To computationally screen tripeptides for dual AChE and BACE-1 inhibition.
• To identify lead compounds for Alzheimer's disease drug development.

Main Methods:

• Machine learning models were used to screen 8000 tripeptides.
• Molecular docking, molecular dynamics, and free energy perturbation analyses were performed.
• ADMET properties were predicted for lead candidates.

Main Results:

• Four top tripeptides (WHM, HMW, WMH, HWM) were identified.
• WHM showed the strongest binding affinity and stability against both AChE and BACE-1.
• WHM demonstrated favorable interactions with key catalytic residues.

Conclusions:

• WHM is a potent dual inhibitor of AChE and BACE-1 with therapeutic potential for Alzheimer's disease.
• Further development of WHM is warranted, considering its predicted ADMET profile.