Designing potential inhibitors for AChE from quinazoline derivatives

We are happy to announce that B.S Thai Quynh Mai and colleagues recently published their work entitled “Designing potential inhibitors for AChE from quinazoline derivatives" in the Journal of Molecular Structure.

Abstract:

Alzheimer's disease (AD), a prevalent chronic neurodegenerative disorder, is associated with the neurotransmitter AChE. The inhibition of AChE can lead to the prevention of AD. In context, quinazoline derivatives were designed considering the structure of AChE active site and the known AChE inhibitory activity of quinazoline derivatives. In particular, the potential inhibitory effects were rapidly and accurately estimated via knowledge- and physics-based methods. Atomistic simulations indicate that quinazoline compounds favorably form π-stacking and sidechain contacts to AChE, implying that vdW dominates electrostatic interaction. It is in excellent agreement with the perturbation simulations since the biological activity of AChE was significantly modified since altering the catalytic triad of the enzyme. It should be noted that the perturbation outcomes suggested that five of six quinazoline derivatives formed a stronger binding affinity, ∆G_FEP ≤ -10.33 kcal mol^-1 compared with the galantamine, ∆G_FEP ≤ -10.02 kcal mol^-1. The experimental works then confirm the computational outcomes that quinazoline derivatives are potential inhibitors of AChE with the obtained IC₅₀  in the range from 302.05 to 1778.59 µM. Furthermore, the compound metrics involve blood-brain barrier, human intestinal absorption, and toxicity of the compounds were also predicted. In addition, both computational and in vitro studies were also performed to estimate the affinity of designed compounds on BACE1. However, the obtained results suggest that quinazoline derivatives play a poor performance over the BACE1 target.