A molecular modeling and 3D QSAR study of a large series of indole inhibitors of human non-pancreatic secretory phospholipase A2

• Published in: European journal of medicinal chemistry 2001, Vol.36 (1), p.1-19
• Main Authors: BERNARD, Philippe, PINTORE, Marco, BERTHON, Jean-Yves, CHRETIEN, Jacques R
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Computer Simulation; Crystallization; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Indoles - chemistry; Indoles - pharmacology; Medical sciences; Models, Molecular; Pancreas - secretion; Pharmacology. Drug treatments; Phospholipases A - antagonists & inhibitors; Phospholipases A - chemistry; Phospholipases A2; Protein Conformation; Reproducibility of Results; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/s0223-5234(00)01183-1

Automated docking allowing protein-based alignment was performed for a series of 188 indole inhibitors of the human non-pancreatic secretory phospholipase A2 (hnps-PLA2). All the substituted indoles were docked to the crystal structure of hnps-PLA2 and a three-dimensional QSAR model was then established using the CoMFA method. The set of 188 compounds was divided into two subsets, the first one constituting the training set (126 compounds), while the second constituted the test set (62 compounds). The established CoMFA model derived from the training set was then applied to the test set. A good correlation between predicted and experimental activity data allows to validate the 3D QSAR model. A second and global 3D QSAR including all the compounds was established, allowing the creation of the hnps-PLA2 pharmacophore.