Enzyme inhibitory activity of marine alkaloid aaptamines for neurodegenerative diseases: An in silico study

The enzyme inhibitory activities of a dataset of 28 aaptamines are
performed to identify potential multifunctional drugs for
neurodegenerative diseases. First, the drug-like properties and
pharmacokinetics (ADMET) study excluded 7 molecules, mostly for the
non-permeability of the blood brain barrier. The binding activities of the
remaining 21 candidates towards acetylcholinesterase (AChE), monoamine
oxidase B (MAOB), and catechol-O-methyltransferase (COMT) enzymes are
initially screened by molecular docking. The top binding complexes
(A12@MAOB, A24@COMT, and A27@AChE) are simultaneously studied by molecular
dynamics in water for 500 ns time-scale, and compared with the references
such as safinamide (SAG), tolcapone (TOL) or donepezil (DON). The results
show that two aaptamines A12 and A27 are well-positioned within the active
pocket of the enzymes, exhibiting structural stability, with an RMSD of
about 0.15-0.2 nm. MM-PBSA calculation indicates that the binding energy
of the ligands to the corresponding targets is equal (A12vs. SAG) or much
lower than the references (A24vs. TOL and A27vs. DON). The van der Waals
interactions contribute more strongly to enzyme binding than the
electrostatic energy. The study results suggest that A27 (lowest binding
energy, -170.42 ± 14.24 kJ mol-1) is the most prominent Aaptamine
candidate for the treatment of neurodegenerative disease.