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.

b Department of Bioinformatics Christ College Rajkot 360 005 Gujarat India

c J Heyrovský Institute of Physical Chemistry Academy of Sciences of the Czech Republic Dolejškova 2155 3 182 23 Prague 8 Czech Republic

Department of Botany Bioinformatics and Climate Change Impacts Management University School of Sciences Gujarat University Ahmedabad 380 009 Gujarat India

e Laboratory of Metabolism Center for Cancer Research National Cancer Institute National Institutes of Health Rockville MD USA

Human Genetics Division Department of Zoology BMTC and HG University School of Sciences Gujarat University Ahmedabad 380009 Gujarat India

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