Background: With the burgeoning worldwide aging population, the incidence of Alzheimer’s disease
(AD) and its associated disorders is continuously rising. To appraise other relevant drug targets that could
lead to potent enzyme targeting, 13 previously predicted ligands (shown favorable binding with AChE (acetylcholinesterase)
and GSK-3 (glycogen synthase kinase) were screened for targeting 3 different enzymes, namely
butyrylcholinesterase (BChE), monoamine oxidase A (MAO-A), and monoamine oxidase B (MAO-B) to possibly
meet the unmet medical need of better AD treatment.
Materials and Methods: The study utilized in silico screening of 13 ligands against BChE, MAO-A and MAOB
using PyRx-Python prescription 0.8. The visualization of the active interaction of studied compounds with targeted
proteins was performed by Discovery Studio 2020 (BIOVIA).
Results: The computational screening of studied ligands revealed the docking energies in the range of -2.4 to
-11.3 kcal/mol for all the studied enzymes. Among the 13 ligands, 8 ligands (55E, 6Z2, 6Z5, BRW, F1B, GVP,
IQ6, and X37) showed the binding energies of ≤ -8.0 kcal/mol towards BChE, MAO-A and MAO-B. The ligand
6Z5 was found to be the most potent inhibitor of BChE and MAO-B, with a binding energy of -9.7 and
-10.4 kcal mol, respectively. Molecular dynamics simulation of BChE-6Z5 and MAO-B-6Z5 complex confirmed
the formation of a stable complex.
Conclusion: Our computational screening, molecular docking, and molecular dynamics simulation studies revealed
that the above-mentioned enzymes targeted ligands might expedite the future design of potent anti-AD
drugs generated on this chemical scaffold.