Abstract
The question of how and why a small molecule binds to a protein is central to ligand-based drug discovery. The traditional way of approaching these questions is pharmacophore analysis. However, pharmacophores as usually applied lack quantitation and subtlety. An improvement is to consider the electrostatic and steric fields of the ligand directly. Molecular fields provide a rich view of the potential interactions that a molecule can make and can be validated through experimental data on molecular interactions and through quantum mechanics calculations. A technique is presented in this review for comparing molecules using molecular fields and assigning similarity scores. This high information content method can be used to align molecules for SAR analysis, to determine the bioactive conformation from ligand data, and to screen large libraries of compounds for structurally unrelated actives. An extension to allow interactive exploration of chemistry space via bioisostere analysis is also reviewed. Examples from the literature showing the success of these methods are presented, and future directions discussed.
Keywords: Molecular field, pharmacophore, alignment, QSAR, bioactive conformation, virtual screening, bioisostere, ligand based design, molecular design, docking
Current Computer-Aided Drug Design
Title: High Content Pharmacophores from Molecular Fields: A Biologically Relevant Method for Comparing and Understanding Ligands
Volume: 7 Issue: 3
Author(s): Timothy J. Cheeseright, Mark D. Mackey and Robert A. Scoffin
Affiliation:
Keywords: Molecular field, pharmacophore, alignment, QSAR, bioactive conformation, virtual screening, bioisostere, ligand based design, molecular design, docking
Abstract: The question of how and why a small molecule binds to a protein is central to ligand-based drug discovery. The traditional way of approaching these questions is pharmacophore analysis. However, pharmacophores as usually applied lack quantitation and subtlety. An improvement is to consider the electrostatic and steric fields of the ligand directly. Molecular fields provide a rich view of the potential interactions that a molecule can make and can be validated through experimental data on molecular interactions and through quantum mechanics calculations. A technique is presented in this review for comparing molecules using molecular fields and assigning similarity scores. This high information content method can be used to align molecules for SAR analysis, to determine the bioactive conformation from ligand data, and to screen large libraries of compounds for structurally unrelated actives. An extension to allow interactive exploration of chemistry space via bioisostere analysis is also reviewed. Examples from the literature showing the success of these methods are presented, and future directions discussed.
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Cite this article as:
J. Cheeseright Timothy, D. Mackey Mark and A. Scoffin Robert, High Content Pharmacophores from Molecular Fields: A Biologically Relevant Method for Comparing and Understanding Ligands, Current Computer-Aided Drug Design 2011; 7 (3) . https://dx.doi.org/10.2174/157340911796504314
DOI https://dx.doi.org/10.2174/157340911796504314 |
Print ISSN 1573-4099 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6697 |
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