Protein-based alignment in 3D QSAR of 26 indole inhibitors of human pancreatic phospholipase A2.
An automated docking procedure was applied on a series of 26 reversible and competitive indole inhibitors of human pancreatic phospholipase A2 (hp-PLA2). X-ray data of this enzyme are not available and the structure was then reconstructed exploiting its protein sequence and the crystallographic data of a bovine pancreatic source. The docking data were used to build a three-dimensional quantitative structure-activity relationship (3D QSAR) model, established using the comparative molecular field analysis (CoMFA) method. This model, joined to the previous one developed for the indole inhibitors of human non-pancreatic secretory phospholipase A2 (hnps-PLA2), an enzyme involved in inflammation processes, will allow for the selection of new strong anti-inflammatory drugs with negligible side effects, at least at the level of hp-PLA2.
Laboratory of Chemometrics & BioInformatics, Faculty of Sciences, University of Orléans, BP 6759, 45067 Cedex 2, Orléans, France.
M
M
Pintore
P
P
Bernard
J Y
JY
Berthon
J R
JR
Chrétien
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002417:Cattle; D003198:Computer Simulation; D003460:Crystallization; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010179:Pancreas / Q000201:enzymology*; D010194:Pancreatin / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013552:Swine
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D010194:Pancreatin; D010741:Phospholipases A; D054467:Phospholipases A2