Abstract
Alzheimer's disease is a topic of deep research interest across the global scientific community. Butyrylcholinesterase (BuChE) is an important enzyme, and an interesting anti-Alzheimer's target. Identification or fresh design of promising BuChE-inhibitors is warranted. Virtual screening supported by molecular dynamics simulations has emerged as a key component of present drug-discovery cascades. The research piece aimed at identification of a putative BuChE-inhibitor as a fresh molecular frame that might aid drug design in the context of Alzheimer's disease. The study utilized 'MCULE' to screen a set of 5 million ligands to test their ability to bind to human BuChE. Pharmacokinetic profiling was achieved by the 'SWISS ADME' program. Toxicities were duly assessed. YASARA STRUCTURE version 20.10.4.W.64 was employed to run 133 ns molecular dynamics (MD) simulation for the complex of 'the top screened out inhibitor' and 'the human BuChE enzyme'. The simulation was executed for approx. 4 days (similar to 93 hrs) on an HP ZR30w workstation. YANACONDA, a special language contained in YASARA STRUCTURE was employed to perform complex tasks. Fine resolution figures (notably the RMSD vs time plot) were created. Snapshots were extracted at every 250 ps. The selected ligand, (3-Bromophenyl)[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl]methanone, exhibited the best overall binding with human BuChE. It interacted with human BuChE through 19 residues. Markedly, 9 of the 19 residues were confirmed to be matching to those of the reference complex (PDB ID 5DYW). Trajectory analysis returned 533 snapshots. The RMSD versus time plot indicated that around 22 ns, equilibrium was achieved and, from then on, the 'BuChE-Top inhibitor' complex remained predominantly stable. From 22 ns and onwards till 133 ns, the backbone RMSD fluctuations were observed to remain limited within a range of 1.2-1.9 angstrom. The molecule, (3-Bromophenyl)[5-(4-chlorophenyl)-5-hydroxy-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl]methanone, satisfied ADMET requirements. Additionally, the feasibility of the proposed enzyme-inhibitor complex was supported by an adequately extended MD simulation of 133 ns. Hence, the proposed molecule could be a likely lead for designing inhibitor(s) against human BuChE. Scope remains for validatory wet laboratory investigation.