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.
Keywords: Consensus scoring, Histamine N-methyltransferase, HipHop, Molecular docking, Structurebased, Virtual screening, Ligand, pharmacophore modeling, Histamine, Hypo1, HNMT, 3D-query, Chembridge databases, ADMET, GPCR, HDC
Letters in Drug Design & Discovery
Title: Ligand and Structure-Based Pharmacophore Modeling for the Discovery of Potential Human HNMT Inhibitors
Volume: 9 Issue: 1
Author(s): Pavadai Elumalai, Hsuan-Liang Liu, Zheng-Li Zhou, Jian-Hua Zhao, Wilson Chen, Chih-Kuang Chuang, Wei-Bor Tsai and Yih Ho
Affiliation:
Keywords: Consensus scoring, Histamine N-methyltransferase, HipHop, Molecular docking, Structurebased, Virtual screening, Ligand, pharmacophore modeling, Histamine, Hypo1, HNMT, 3D-query, Chembridge databases, ADMET, GPCR, HDC
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.
Export Options
About this article
Cite this article as:
Elumalai Pavadai, Liu Hsuan-Liang, Zhou Zheng-Li, Zhao Jian-Hua, Chen Wilson, Chuang Chih-Kuang, Tsai Wei-Bor and Ho Yih, Ligand and Structure-Based Pharmacophore Modeling for the Discovery of Potential Human HNMT Inhibitors, Letters in Drug Design & Discovery 2012; 9 (1) . https://dx.doi.org/10.2174/157018012798192955
DOI https://dx.doi.org/10.2174/157018012798192955 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Clearance of Amyloid-β Peptide by Neuronal and Non-Neuronal Cells: Proteolytic Degradation by Secreted and Membrane associated Proteases
Current Neurovascular Research Current Ocular Drug Delivery Challenges for N-acetylcarnosine: Novel Patented Routes and Modes of Delivery, Design for Enhancement of Therapeutic Activity and Drug Delivery Relationships
Recent Patents on Drug Delivery & Formulation Development of HIV-1 Fusion Inhibitors Targeting gp41
Current Medicinal Chemistry Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA)
Current Neuropharmacology Calorie Restriction and Dietary Restriction Mimetics: A Strategy for Improving Healthy Aging and Longevity
Current Pharmaceutical Design Buccal Delivery of Methimazole as an Alternative Means for Improvement of Drug Bioavailability: Permeation Studies and Matrix System Design
Current Pharmaceutical Design De Novo DNMTs and DNA Methylation: Novel Insights into Disease Pathogenesis and Therapy from Epigenomics
Current Pharmaceutical Design Metformin and Energy Metabolism in Breast Cancer: From Insulin Physiology to Tumour-initiating Stem Cells
Current Molecular Medicine Transmission of HIV-1 in the Face of Neutralizing Antibodies
Current HIV Research Endoplasmic Reticulum Protein Quality Control in Neurodegenerative Disease: The Good, the Bad and the Therapy
Current Medicinal Chemistry Viral Entry Inhibitors Targeting Six-Helical Bundle Core against Highly Pathogenic Enveloped Viruses with Class I Fusion Proteins
Current Medicinal Chemistry Could Better Phenotyping Small Vessel Disease Provide New Insights into Alzheimer Disease and Improve Clinical Trial Outcomes?
Current Alzheimer Research Molecular Targets of Ovarian Carcinomas with Acquired Resistance to Platinum/Taxane Chemotherapy
Current Cancer Drug Targets Adenosine A<sub>2A</sub> Receptor Antagonists as Positron Emission Tomography (PET) Tracers
Current Medicinal Chemistry Non-canonical Molecular Targets for Novel Analgesics: Intracellular Calcium and HCN Channels
Current Neuropharmacology The Potential and Limitations of p38MAPK as a Drug Target for the Treatment of Hematological Malignancies
Current Drug Targets Anti-Inflammatory Drug Targeting in Asthma. Should Inhaled Corticosteroids Reach the Small Airways?
Current Drug Therapy MicroRNAs: Regulators of TLR2-Mediated Probiotic Immune Responses
MicroRNA Potential Therapeutic Interest of Adenosine A2A Receptors in Psychiatric Disorders
Current Pharmaceutical Design The Critical Role of Vascular Endothelial Growth Factor in Tumor Angiogenesis
Current Cancer Drug Targets