TY - JOUR

T1 - Molecular determinants of ligand binding modes in the histamine H 4 receptor

T2 - Linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies

AU - Istyastono, Enade P.

AU - Nijmeijer, Saskia

AU - Lim, Herman D.

AU - Van De Stolpe, Andrea

AU - Roumen, Luc

AU - Kooistra, Albert J.

AU - Vischer, Henry F.

AU - De Esch, Iwan J.P.

AU - Leurs, Rob

AU - De Graaf, Chris

PY - 2011/12/8

Y1 - 2011/12/8

N2 - The histamine H 4 receptor (H 4R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H 3 receptor (H 3R), two acidic residues in the H 4R binding pocket, D 3.32 and E 5.46, act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H 4R ligands. Given the symmetric distribution of these complementary pharmacophore features in H 4R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H 4R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5) -imidazolyl)propyl]isothiourea) derivatives to investigate H 4R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H 4R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H 4R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H 4R and can be used as a general approach to elucidate the structure of protein-ligand complexes.

AB - The histamine H 4 receptor (H 4R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H 3 receptor (H 3R), two acidic residues in the H 4R binding pocket, D 3.32 and E 5.46, act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H 4R ligands. Given the symmetric distribution of these complementary pharmacophore features in H 4R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H 4R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5) -imidazolyl)propyl]isothiourea) derivatives to investigate H 4R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H 4R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H 4R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H 4R and can be used as a general approach to elucidate the structure of protein-ligand complexes.

UR - http://www.scopus.com/inward/record.url?scp=82555185524&partnerID=8YFLogxK

U2 - 10.1021/jm201042n

DO - 10.1021/jm201042n

M3 - Journal article

C2 - 22003888

AN - SCOPUS:82555185524

VL - 54

SP - 8136

EP - 8147

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 23

ER -