A new crystal structure fragment-based pharmacophore method for G protein-coupled receptors

• Published in: Methods (San Diego, Calif.) Vol. 71; pp. 104 - 112
• Main Authors: Fidom, Kimberley, Isberg, Vignir, Hauser, Alexander S., Mordalski, Stefan, Lehto, Thomas, Bojarski, Andrzej J., Gloriam, David E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2015
• Subjects: Crystallography, X-Ray - methods; Drug discovery; Fragment-based drug design; G protein-coupled receptor; Ligands; Models, Molecular; Pharmacophore; Protein Structure, Tertiary; Receptors, G-Protein-Coupled - chemistry; Virtual screening; AFE; G protein-coupled receptor; AFF; ROC plot; HBA; Virtual screening; H1; H3; HBD; AUC; ECL; 7TM; Fragment-based drug design; GPCR; TM; Drug discovery; Pharmacophore
• ISSN: 1046-2023; 1095-9130
• DOI: 10.1016/j.ymeth.2014.09.009

•A new pharmacophore method for G protein-coupled receptors is presented.•We extracted a library of 250 crystal structure fragments: interacting moiety–sidechain pairs.•Pharmacophores are built by recombining fragments from different ligands and targets.•Validation was made by virtual screening of histamine H1 and H3 receptor pharmacophores.•A GPCRDB tool was developed to match and superimpose fragments to any target. We have developed a new method for the building of pharmacophores for G protein-coupled receptors, a major drug target family. The method is a combination of the ligand- and target-based pharmacophore methods and founded on the extraction of structural fragments, interacting ligand moiety and receptor residue pairs, from crystal structure complexes. We describe the procedure to collect a library with more than 250 fragments covering 29 residue positions within the generic transmembrane binding pocket. We describe how the library fragments are recombined and inferred to build pharmacophores for new targets. A validating retrospective virtual screening of histamine H1 and H3 receptor pharmacophores yielded area-under-the-curves of 0.88 and 0.82, respectively. The fragment-based method has the unique advantage that it can be applied to targets for which no (homologous) crystal structures or ligands are known. 47% of the class A G protein-coupled receptors can be targeted with at least four-element pharmacophores. The fragment libraries can also be used to grow known ligands or for rotamer refinement of homology models. Researchers can download the complete fragment library or a subset matching their receptor of interest using our new tool in GPCRDB.