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 conformational analysis and 3D-QSAR methods of identify molecular features common to a series of hydroxyacetophenone (HAP) and non-hydroxyacetophenone (non-HAP) peptide leukotriene (pLT) receptor antagonists. In attempts to develop a ligand-binding model for the pLT receptor, the Apex-3D program was used to identify biophoric structural patterns that are common to 13 diverse sets of compounds showing different levels of biological activity. A systematic conformational analysis was carried out to obtain sterically accessible conformations for these flexible compounds. Apex-3D was then utilized to propose common biophoric regions based on the selection of one of several conformations (MOPAC-minimized AM1) from each compound's data set that best fits the biophoric pattern and the resulting superimposition with all the other data-set compounds. Apex-3D identified three common biophoric features important for 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 plane 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 be useful in designing new pLT antagonists. Molecular volumes and electrostatic potential similarities were also calculated in order to obtain the important structural requirements for the activity.
Hariprasad
V
V
Department of Chemical Technology, University of Bombay, Matunga, India.
Kulkarni
V M
VM
D000098:Acetophenones / Q000737:chemistry; D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D020024:Leukotriene Antagonists; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000098:Acetophenones; D020024:Leukotriene Antagonists; D008024:Ligands; D010455:Peptides