title: Development of a three-dimensional CysLT1 (LTD4) antagonist model with an incorporated amino acid residue from the receptor.
abstract: This paper describes the molecular modeling of leukotriene CysLT1 (or LTD4) receptor antagonists. Several different structural classes of CysLT1 antagonists were superimposed onto the new and highly rigid CysLT1 antagonist 8-carboxy-3'-[2-(2-quinolinyl)ethenyl]flavone (1, VUF 5017) to generate a common pharmacophoric arrangement. On the basis of known structure-activity relationships of CysLT1 antagonists, the quinoline nitrogen (or a bioisosteric equivalent thereof) and an acidic function were taken as the matching points. In order to optimize the fitting of acidic moieties of all antagonists, an arginine residue from the receptor was proposed as the interaction site for the acidic moieties. Incorporation of this amino acid residue into the model revealed additional interactions between the guanidine group and the nitrogen atoms of quinoline-containing CysLT1 antagonists. In some cases, the arginine may even interact with pi-clouds of phenyl residues of CysLT1 antagonists. The alignment of Montelukast (MK-476) suggests the presence of an additional pocket in the binding site for CysLT1 antagonists. The derived model should be useful for a better understanding of the molecular recognition of the leukotriene CysLT1 receptor.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Zwaagstra
authors.forename: S H
authors.initials: SH
authors.lastname: Schoenmakers
authors.forename: P H
authors.initials: PH
authors.lastname: Nederkoorn
authors.forename: E
authors.initials: E
authors.lastname: Gelens
authors.forename: H
authors.initials: H
authors.lastname: Timmerman
authors.forename: M Q
authors.initials: MQ
authors.lastname: Zhang
mesh_terms: D001120:Arginine / Q000737:chemistry* / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D008958:Models, Molecular; D008968:Molecular Conformation; D011804:Quinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000737:chemistry / Q000378:metabolism
chemical_list: D005419:Flavonoids; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D011804:Quinolines; D018077:Receptors, Leukotriene; C111913:VUF 5017; D001120:Arginine; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor