A PROPOSED COMMON SPATIAL PHARMACOPHORE AND THE CORRESPONDING ACTIVE CONFORMATIONS OF SOME PEPTIDE LEUKOTRIENE RECEPTOR ANTAGONISTS

Molecular modeling studies were carried out by a combined use of confo rmational analysis and 3D-QSAR methods to identify molecular features common to a series of hydroxyacetophenone (HAP) and non-hydroxyacetoph enone (non-HAP) peptide leukotriene (pLT) receptor antagonists, In att empts to develop a ligand-binding model for the pLT receptor, the Apex -3D program was used to identify biophoric structural patterns that ar e common to 13 diverse sets of compounds showing different levels of b iological activity. A systematic conformational analysis was carried o ut to obtain sterically accessible conformations for these flexible co mpounds. Apex-3D was then utilized to propose common biophoric regions based on the selection of one of several conformations (MOPAC-minimiz ed AM1) from each compound's data set that best fits the biophoric pat tern and the resulting superimposition with all the other data-set com pounds. Apex-3D identified three common biophoric features important f or activity: one as the hydroxyl, acetyl, carbonyl and carboxyl groups , which mimic the acid-binding region of an agonist, the other as the hydrogen-bond donating site, and the third part is represented by a pl ane in which lipophilic aromatic groups align. The structure-activity relationships were then assessed by using the 3D-QSAR model. A common biophore model is proposed from the Apex-3D analysis which may he usef ul in designing new pLT antagonists. Molecular volumes and electrostat ic potential similarities were also calculated in order to obtain the important structural requirements for the activity.