Development of a three-dimensional CysLT1 (LTD4) antagonist model with an incorporated amino acid residue from the receptor

This paper describes the molecular modeling of leukotriene CysLT(1) (or LTD4) receptor antagonists. Several different structural classes of CysLT(1) antagonists were superimposed onto the new and highly rigid CysLT(1) 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 CysLT(1) 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 CysLT(1) antagonists. In some cases, the arginine may even interact with pi-clouds of phenyl residues of CysLT(1) antagonists. The alignment of Montelukast (MK-476) suggests the presence of an additional pocket in the binding site for CysLT(1) antagonists. The derived model should be useful for a better understanding of the molecular recognition of the leukotriene CysLT(1) receptor.