Sequence-Derived Three-Dimensional Pharmacophore Models for G-Protein-Coupled Receptors and Their Application in Virtual Screening

Abstract

G-protein-coupled receptors (GPCRs) comprise a large protein family of significant past and current interest of pharmaceutical research. X-ray crystallography and molecular modeling combined with site-directed mutagenesis studies suggest that most family A GPCRs share a small-molecule binding site located in the outer part of the seven-transmembrane (7TM) bundle. Here we describe an automated method to derive sequence-derived three-dimensional (3D) pharmacophore models capturing the key elements for addressing this binding site by a small-molecule ligand. We have generated structure-based pharmacophore models from 10 homology models and 3 X-ray structures of receptor-ligand complexes. These 13 pharmacophores have been dissected into 35 different single-feature pharmacophore elements, each associated with a sequence motif or chemoprint, describing its molecular interaction partner(s) in the receptor. Subsequently, the protein sequences of 270 GPCRs have been searched for the presence of chemoprints and the appropriate single-feature pharmacophores have been assembled into three- to seven-feature 3D-pharmacophore models for each human family A GPCR. These models can be applied for virtual screening and for the design of subfamily directed libraries. A case study demonstrates the successful application of this approach for the identification of potent agonists for the complement component 3a receptor 1 (C3AR1) by virtual screening.

Pharmacophore Modeling: Methods and Applications

“…Even in the absence of a known structure, homology models may be productively used, as has been done for serotonin transporters [45] and G-protein-coupled receptors [46,47]. Receptor-based elucidation was recently comprehensively reviewed [48].…”

From Three-Dimensional GPCR Structure to Rational Ligand Discovery

“…In some GPCR SBVS studies docking based screening simulations have been guided by pharmacophore constraints Evers and Klebe 2004;Sirci et al 2012). Pharmacophore models and/or exclusion constraints derived from structural models of receptor-ligand complexes (or the receptor alone) can be used as an alternative structure-based virtual screening approach to molecular docking simulations, as demonstrated in several successful GPCR SBVS campaigns to discover ligands of CA3R (Klabunde et al 2009), CNR2 (Salo et al 2005), FFAR1 (Tikhonova et al 2008), FPR1R (Edwards et al 2005), MCHR1 (Cavasotto et al 2008), HRH3 (Sirci et al 2012). …”

“…ligand-based similarity (2D and 3D), and receptor/ligand-based pharmacophore searches (Kellenberger et al 2007;Cavasotto et al 2008;Tikhonova et al 2008;Klabunde et al 2009;Salo et al 2005;Edwards et al 2005)). For 3D similarity and receptor-based pharmacophore searches the receptor-bound conformation of reference compounds can be derived from docking simulations in the receptor model.…”

Receptor Chemoprint Derived Pharmacophore Model for Development of CAIX Inhibitors

“…This technique is more suitable, when protein structure or its complex with ligand has limited information [15]. Therefore, the physicochemical properties and spatial position of the active site residues of a receptor, so called "chemoprint" could be a new endeavour for the development of receptor specific potential inhibitors [16].…”