Nguyen_2025_R.Soc.Open.Sci_12_250697

The enzyme inhibitory activities of a dataset of 28 aaptamines are performed to identify potential multifunctional drugs for neurodegenerative diseases (NDs). First, the drug-like properties and pharmacokinetic (ADMET) study excluded seven 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 a root mean square deviation of about 0.15-0.2 nm. MM-PBSA calculation indicates that the binding energy of the ligands to the corresponding targets is equal to (A12 versus SAG) or much lower than the references (A24 versus TOL and A27 versus 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 NDs.