DEVELOPMENT OF A 3-DIMENSIONAL CYSLT(1) (LTD4) ANTAGONIST MODEL WITH AN INCORPORATED AMINO-ACID RESIDUE FROM THE RECEPTOR

This paper describes the molecular modeling of leukotriene CysLT(1) (o r LTD4) receptor antagonists. Several different structural classes of CysLT(1) antagonists were superimposed onto the new and highly rigid C ysLT(1) antagonist 8-carboxy-3'-[2-(2-quinolinyl)ethenyl]flavone (1, V UF 5017) to generate a common pharmacophoric arrangement. On the basis of known structure-activity relationships of CysLT(1) antagonists, th e quinoline nitrogen (or a bioisosteric equivalent thereof) and an aci dic function were taken as the matching points. In order to optimize t he 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 reve aled additional interactions between the guanidine group and the nitro gen atoms of quinoline-containing CysLT(1) antagonists. In some cases, the arginine may even interact with pi-clouds of phenyl residues of C ysLT(1) antagonists. The alignment of Montelukast (MK-476) suggests th e presence of an additional pocket in the binding site for CysLT(1) an tagonists. The derived model should be useful for a better understandi ng of the molecular recognition of the leukotriene CysLT(1) receptor.