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Journal of Computer-Aided Molecular Design
Article . 2014 . Peer-reviewed
License: Springer TDM
Data sources: Crossref
DBLP
Article
Data sources: DBLP
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Site-Identification by Ligand Competitive Saturation (SILCS) assisted pharmacophore modeling

Authors: Wenbo Yu 0002; Sirish Kaushik Lakkaraju; E. Prabhu Raman; Alexander D. MacKerell Jr.;

Site-Identification by Ligand Competitive Saturation (SILCS) assisted pharmacophore modeling

Abstract

Database screening using receptor-based pharmacophores is a computer-aided drug design technique that uses the structure of the target molecule (i.e. protein) to identify novel ligands that may bind to the target. Typically receptor-based pharmacophore modeling methods only consider a single or limited number of receptor conformations and map out the favorable binding patterns in vacuum or with a limited representation of the aqueous solvent environment, such that they may suffer from neglect of protein flexibility and desolvation effects. Site-Identification by Ligand Competitive Saturation (SILCS) is an approach that takes into account these, as well as other, properties to determine 3-dimensional maps of the functional group-binding patterns on a target receptor (i.e. FragMaps). In this study, a method to use the FragMaps to automatically generate receptor-based pharmacophore models is presented. It converts the FragMaps into SILCS pharmacophore features including aromatic, aliphatic, hydrogen-bond donor and acceptor chemical functionalities. The method generates multiple pharmacophore hypotheses that are then quantitatively ranked using SILCS grid free energies. The pharmacophore model generation protocol is validated using three different protein targets, including using the resulting models in virtual screening. Improved performance and efficiency of the SILCS derived pharmacophore models as compared to published docking studies, as well as a recently developed receptor-based pharmacophore modeling method is shown, indicating the potential utility of the approach in rational drug design.

Keywords

Models, Chemical, Drug Design, Cluster Analysis, Ligands

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
59
Top 10%
Top 10%
Top 10%
bronze