Pharmacophore-based virtual screening of catechol-o-methyltransferase (COMT) inhibitors to combat Alzheimer’s disease

0484458 - ÚFCH JH 2019 RIV US eng J - Journal Article
Patel, Ch. N. - Georrge, J. J. - Modi, Krunal M. - Narechania, M. B. - Patel, D. P. - Gonzalez, F. J. - Pandya, H. A.
Pharmacophore-based virtual screening of catechol-o-methyltransferase (COMT) inhibitors to combat Alzheimer’s disease.
Journal of Biomolecular Structure & Dynamics. Roč. 36, č. 15 (2018), s. 3938-3957. ISSN 0739-1102
Institutional support: RVO:61388955
Keywords : Alzheimer’s disease (AD) * catechol-o-methyltransferase (COMT) * pharmacophore
OECD category: Physical chemistry
Impact factor: 3.310, year: 2018

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.
Permanent Link: http://hdl.handle.net/11104/0279617