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Issue 1, 2012
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From the protein's perspective: the benefits and challenges of protein structure-based pharmacophore modeling

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Abstract

A pharmacophore describes the arrangement of molecular features a ligand must contain to efficaciously bind a receptor. Pharmacophore models are developed to improve molecular understanding of ligandprotein interactions, and can be used as a tool to identify novel compounds that fulfil the pharmacophore requirements and have a high probability of being biologically active. Protein structure-based pharmacophores (SBPs) derive these molecular features by conversion of protein properties to reciprocal ligand space. Unlike ligand-based pharmacophore models, which require templates of ligands in their bioactive conformation, SBPs do not depend on ligand information. The current review describes the different steps in the construction of SBPs: (i) protein structure preparation, (ii) binding site detection, (iii) pharmacophore feature definition, and (iv) pharmacophore feature selection. We show that the SBP modeling workflow poses different challenges than ligand-based pharmacophore modeling, including the definition of protein pharmacophore features essential for ligand binding. A comprehensive overview of different SBP modeling and screening methods and applications is provided to illustrate that SBPs can be efficiently used for virtual screening, ligand binding mode prediction, and binding site similarity detection. Our review demonstrates that SBPs are valuable tools for hit and lead optimization, compound library design and target hopping, especially in cases where ligand information is scarce.

Graphical abstract: From the protein's perspective: the benefits and challenges of protein structure-based pharmacophore modeling

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Publication details

The article was received on 17 Aug 2011, accepted on 08 Nov 2011 and first published on 12 Dec 2011


Article type: Review Article
DOI: 10.1039/C1MD00210D
Citation: Med. Chem. Commun., 2012,3, 28-38
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    From the protein's perspective: the benefits and challenges of protein structure-based pharmacophore modeling

    M. P. A. Sanders, R. McGuire, L. Roumen, I. J. P. de Esch, J. de Vlieg, J. P. G. Klomp and C. de Graaf, Med. Chem. Commun., 2012, 3, 28
    DOI: 10.1039/C1MD00210D

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