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

TY - JOUR

T1 - A new crystal structure fragment-based pharmacophore method for G protein-coupled receptors

AU - Fidom, Kimberley

AU - Isberg, Vignir

AU - Hauser, Alexander Sebastian

AU - Mordalski, Stefan

AU - Lehto, Thomas

AU - Bojarski, Andrzej J

AU - Gloriam, David E

N1 - Copyright © 2014. Published by Elsevier Inc.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

U2 - 10.1016/j.ymeth.2014.09.009

DO - 10.1016/j.ymeth.2014.09.009

M3 - Journal article

C2 - 25286328

SN - 1046-2023

VL - 71

SP - 104

EP - 112

JO - Methods

JF - Methods

ER -