Ligand and structure-based pharmacophore modeling for the discovery of potential human HNMT inhibitors
Journal
Letters in Drug Design and Discovery
Journal Volume
9
Journal Issue
1
Pages
17-29
Date Issued
2012
Author(s)
Abstract
The inhibition of Histamine N-methyltransferase (HNMT) has been recently shown to play potential roles in the treatment of neurodegenerative diseases, allergic vasoconstriction and anaphylactic manifestation. For designing and discovering new potential human HNMT inhibitors, the ligand (Hypo1) and structure-based (SB-Hypo1) pharmacophore models were developed based on the most active inhibitors and the highest resolution crystal structure of HNMT, respectively. After validating the reliability of both models with decoy dataset, they were separately used as 3D-query for virtual screening to retrieve potential hits from Maybridge and Chembridge databases. Subsequently, the hit compounds were subjected to filter by applying the ADMET, molecular docking and consensus score. Finally, 10 hits (five compounds from each model) were suggested as potential leads based on the structural diversity, good fit value, favorable binding interactions and high docking consensus score. The obtained novel hits from this study may facilitate to identify and optimize new leads for HNMT inhibition. ? 2012 Bentham Science Publishers.
Subjects
Consensus scoring; HipHop; Histamine N-methyltransferase; Molecular docking; Pharmacophore model; Structure-based; Virtual screening
SDGs
Other Subjects
amodiaquine; diphenhydramine; histamine methyltransferase; ligand; mepacrine; methyltransferase inhibitor; metodiclorofen; tacrine; article; controlled study; crystal structure; data base; drug absorption; drug binding; drug design; drug development; drug distribution; drug elimination; drug interaction; drug metabolism; drug potency; drug screening; drug toxicity; human; molecular docking; molecular model; pharmacophore; priority journal; validation process
Type
journal article