Journal of Computer-Aided Molecular Design

, Volume 28, Issue 5, pp 491–507

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

  • Wenbo Yu
  • Sirish Kaushik Lakkaraju
  • E. Prabhu Raman
  • Alexander D. MacKerellJr.
Article

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

Computer Virtual screening Drug design Lead discovery Enrichment 

Supplementary material

10822_2014_9728_MOESM1_ESM.pdf (1.7 mb)
Table including parameters used to develop SILCS pharmacophore models, a figure and description of the DHFR FragMaps generated in the present study and ROC plots of VS results using docking and pharmacophore modeling methods. (PDF 1720 kb)

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Wenbo Yu
    • 1
  • Sirish Kaushik Lakkaraju
    • 1
  • E. Prabhu Raman
    • 1
  • Alexander D. MacKerellJr.
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyUniversity of MarylandBaltimoreUSA

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