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

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          Abstract

          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.

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          Author and article information

          Journal
          8404176
          1462
          J Biomol Struct Dyn
          J. Biomol. Struct. Dyn.
          Journal of biomolecular structure & dynamics
          0739-1102
          1538-0254
          7 January 2019
          27 December 2017
          November 2018
          12 February 2019
          : 36
          : 15
          : 3938-3957
          Affiliations
          [a ]Department of Botany, Bioinformatics and Climate Change Impacts Management, University School of Sciences, Gujarat University, Ahmedabad 380 009, Gujarat, India
          [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 Republi
          [d ]Human Genetics Division, Department of Zoology, BMTC and HG, University School of Sciences (USSC), Gujarat University, Ahmedabad 380009, Gujarat, India
          [e ]Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
          Author notes
          Article
          PMC6371058 PMC6371058 6371058 nihpa1000727
          10.1080/07391102.2017.1404931
          6371058
          29281938
          246cc241-a1ed-4cbb-9da7-e07fae84aae4
          History
          Categories
          Article

          ZINC pharmer,molecular dynamics,Alzheimer’s disease (AD),catechol-o-methyltransferase (COMT),pharmacophore,ADMET

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