Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1

Andrey Ivanovich Khlebnikov, Igor A. Schepetkin, Liliya N. Kirpotina, Lars Brive, Claes Dahlgren, Mark A. Jutila, Mark T. Quinn

Результат исследований: Материалы для журналаСтатья

14 Цитирования (Scopus)

Выдержка

Human N-formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor (GPCR) involved in host defense and sensing cellular damage. Since structurebased ligand design for many GPCRs, including FPR1, is restricted by the lack of experimental three dimensional structures, homology modeling has been widely used to study GPCR-ligand binding. Indeed, receptor-ligand binding mode predictions can be derived from homology modeling with supporting ligand information. In the present work, we report comparative docking studies of 2-(benzimidazol-2-ylthio)-N-phenylacetamide derived FPR1 agonists, identified here and previously, with several known FPR1 peptide agonists in a FPR1 homology model that is based on the crystal structure of bovine rhodopsin. We found that the binding pocket of the most active molecules shares some common features with high affinity FPR1 peptide agonists, suggesting that they may bind to similar binding sites. Classification tree analysis led to the derivation of a good recognition model based on four amino acid descriptors for distinguishing FPR1 ligands from inactive analogs. Hence, the corresponding residues (Thr199, Arg201, Gly202, and Ala261) can be considered as markers of important areas in the ligand binding site. Concurrently, we identified several unique binding features of benzimidazole derivatives and showed that alkoxysubstituents of the benzimidazole ring are located within a FPR1 hole bounded by Thr199, Thr265, Ile268, and Leu271 or in a groove in the vicinity of Leu198, Arg201, Gly202, and Arg205. The understanding of these molecular features will likely prove beneficial in future design of novel FPR1 agonists based on the benzimidazole scaffold.

Язык оригиналаАнглийский
Страницы (с-по)2831-2843
Число страниц13
ЖурналJournal of Molecular Modeling
Том18
Номер выпуска6
DOI
СостояниеОпубликовано - июн 2012
Опубликовано для внешнего пользованияДа

Отпечаток

Formyl Peptide Receptor
Peptides
peptides
Molecules
Ligands
molecules
ligands
homology
G-Protein-Coupled Receptors
Binding sites
Binding Sites
acetanilide
human FPR1 protein
Rhodopsin
Proteins
proteins
Scaffolds
Scaffolds (biology)
Crystal structure
grooves

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Computer Science Applications
  • Computational Theory and Mathematics
  • Catalysis
  • Organic Chemistry
  • Inorganic Chemistry

Цитировать

Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1. / Khlebnikov, Andrey Ivanovich; Schepetkin, Igor A.; Kirpotina, Liliya N.; Brive, Lars; Dahlgren, Claes; Jutila, Mark A.; Quinn, Mark T.

В: Journal of Molecular Modeling, Том 18, № 6, 06.2012, стр. 2831-2843.

Результат исследований: Материалы для журналаСтатья

Khlebnikov, Andrey Ivanovich ; Schepetkin, Igor A. ; Kirpotina, Liliya N. ; Brive, Lars ; Dahlgren, Claes ; Jutila, Mark A. ; Quinn, Mark T. / Molecular docking of 2-(benzimidazol-2-ylthio)-N-phenylacetamide-derived small-molecule agonists of human formyl peptide receptor 1. В: Journal of Molecular Modeling. 2012 ; Том 18, № 6. стр. 2831-2843.
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abstract = "Human N-formyl peptide receptor 1 (FPR1) is a G protein-coupled receptor (GPCR) involved in host defense and sensing cellular damage. Since structurebased ligand design for many GPCRs, including FPR1, is restricted by the lack of experimental three dimensional structures, homology modeling has been widely used to study GPCR-ligand binding. Indeed, receptor-ligand binding mode predictions can be derived from homology modeling with supporting ligand information. In the present work, we report comparative docking studies of 2-(benzimidazol-2-ylthio)-N-phenylacetamide derived FPR1 agonists, identified here and previously, with several known FPR1 peptide agonists in a FPR1 homology model that is based on the crystal structure of bovine rhodopsin. We found that the binding pocket of the most active molecules shares some common features with high affinity FPR1 peptide agonists, suggesting that they may bind to similar binding sites. Classification tree analysis led to the derivation of a good recognition model based on four amino acid descriptors for distinguishing FPR1 ligands from inactive analogs. Hence, the corresponding residues (Thr199, Arg201, Gly202, and Ala261) can be considered as markers of important areas in the ligand binding site. Concurrently, we identified several unique binding features of benzimidazole derivatives and showed that alkoxysubstituents of the benzimidazole ring are located within a FPR1 hole bounded by Thr199, Thr265, Ile268, and Leu271 or in a groove in the vicinity of Leu198, Arg201, Gly202, and Arg205. The understanding of these molecular features will likely prove beneficial in future design of novel FPR1 agonists based on the benzimidazole scaffold.",
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AU - Khlebnikov, Andrey Ivanovich

AU - Schepetkin, Igor A.

AU - Kirpotina, Liliya N.

AU - Brive, Lars

AU - Dahlgren, Claes

AU - Jutila, Mark A.

AU - Quinn, Mark T.

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