Alzheimer's disease (AD) is one of the most significant neurodegenerative disorders and its symptoms mostly appear in aged people. Catechol-o-methyltransferase (COMT) is one of the known target enzymes responsible for AD. With the use of 23 known inhibitors of COMT, a query has been generated and validated by screening against the database of 1500 decoys to obtain the GH score and enrichment value. The crucial features of the known inhibitors were evaluated by the online ZINC Pharmer to identify new leads from a ZINC database. Five hundred hits were retrieved from ZINC Pharmer and by ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering by using FAF-Drug-3 and 36 molecules were considered for molecular docking. From the COMT inhibitors, opicapone, fenoldopam, and quercetin were selected, while ZINC63625100_413 ZINC39411941_412, ZINC63234426_254, ZINC63637968_451, and ZINC64019452_303 were chosen for the molecular dynamics simulation analysis having high binding affinity and structural recognition. This study identified the potential COMT inhibitors through pharmacophore-based inhibitor screening leading to a more complete understanding of molecular-level interactions.
Keywords: AD; Alzheimer’s disease; ADMET; ADMET; Absorption, Distribution, Metabolism, Excretion, and Toxicity; AR; Aromatic Ring; Alzheimer’s disease (AD); COMT; Catechol-O-Methyltransferase; DNC; 3, 5-dinitrocatechol; DUDE; A Database of Useful (Docking) Decoys-Enhanced; FAF; Drug3-Free ADME-Tox Filtering Tool; GH; Güner-Henry; HBA; Hydrogen Bond Acceptor; HBD; Hydrogen Bond Donor; HYP; Hydrophobic; MD; Molecular Dynamics; MMFF94; Merck Molecular Force Field94; Mg+2; Magnesium ion; PD; Parkinson’s disease; PDB; Protein Data Bank; RDF; Radial Distribution Function; RMSD; Root-mean-square-deviation; RMSF; Root-mean-square Fluctuations; SAM; S-Adenosyl L- Methionine; YASARA; Yet Another Scientific Artificial Reality Application; ZINC pharmer; ZINC39411941_412; (N-[3-[(2R)-5-benzoyl-2H-benzimidazol-2-yl]phenyl]cyclopropanecarboxamide); ZINC63234426_254; ((4S)-4-(2H-benzimidazol-2-yl)-1-(1-naphthyl) pyrrolidin-2-one); ZINC63625100_413; ((2R)-N-[3-[2-(2H-benzimidazol-2-yl)ethyl]phenyl]-2H-indole-2-carboxamide); ZINC63637968_451; (N-[2-(2H-benzimidazol-2-yl)phenyl]-4-benzylbenzamide); ZINC64019452_303; (2-(2H-benzimidazol-2-yl)-N-phenethyl-benzamide); catechol-o-methyltransferase (COMT); molecular dynamics; pharmacophore.