A proposed common spatial pharmacophore and the corresponding active conformations of some peptide leukotriene receptor antagonists

Abstract

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.

Subsite specificity of trypanosomal cathepsin L‐like cysteine proteases

“…The theoretical values of volume (Å 3 ) and hydrophobicity (expressed as partition coefficient in octanol/water; logP) of scored Phe analogs were calculated, respectively, with apex ‐3 d and 3 d ‐ qsar ( insight ii ), according to Hariprasad & Kulkarni [37] (Table 4). No correlation was observed between residue volumes and ludi link scores.…”

“…The same approach was made with the superimposed congopain structure. The volume (Å 3 ) and the partition coefficient in octanol/water (logP) of phenylalanine structural derivatives were calculated, according to Hariprasad & Kulkarni [37], respectively, with apex ‐3 d and 3 d ‐ qsar ( insight ii ), running on a Silicon Graphics Indigo 2 workstation.…”

Three-Dimensional Quantitative Structure−Activity Relationship (QSAR) and Receptor Mapping of Cytochrome P-45014αDM Inhibiting Azole Antifungal Agents

“…To filter out conformers that will not add new information on biophore geometry and resultant superimpositioning of these flexible ligands, Apex-3D was then used for internal conformer clusterization in which the sample of conformers for each compound is partitioned into a number of clusters. 22 After the conformer clustering, the lowest energy conformer of each cluster is selected as representative of that cluster and exported to Apex-3D, which is available in INSIGHT II (95.0) software for automated biophore identification and 3D-QSAR model building. Having determined the lowest energy state of each of the compounds, the energy of each compound when it was in the pharmacophoric configuration was calculated and compared to determine whether the pharmacophoric conformation was a viable entity or a modeling artifact and shown in Table 1.…”

Modeling and Informatics in Drug Design

“…Figure 1.4 shows a typical contour map from CoMFA analysis. CoMSIA [42] , CoMMA [44] , GRID [47] , molecular shape analysis (MSA) [48] , comparative receptor surface analysis (CoRSA) [49] , and Apex -3D [50] are other 3D QSAR methods that are being employed successfully.…”