title: Quantitative structure-activity relationship (QSAR) analysis of a series of indole analogues as inhibitor for human group V secretory phospholipase A2.
abstract: Phospholipase A2s (PLA2) are a class of enzymes, which catalyze the hydrolysis of membrane phospholipids at the sn-2 position to release fatty acids and lysophospholipids. When the fatty acid is arachidonic acid (AA), a complementary metabolism leads to pro-inflammatory mediators collectively known as eicosanoids. Thus, inhibiting PLA2 activity remains a prime target for the development of new drugs for the treatment of inflammation-related diseases. More than one type of PLA2s plays a major role in inflammatory disease conditions. In the present study, quantitative structure-activity relationship (QSAR) study was performed for a series of 48 Me-indoxam derivatives as human group V PLA, (hVPLA2) inhibitors, using molecular operating environment (MOE) software. The hVPLA2 is a secretory PLA2 (sPLA2), involved in eicosanoid formation in inflammatory cells such as macrophages and mast cells. These studies have come out with three good predictive models (r = 0.82-0.84), which are cross-validated (rcv = 0.68-0.70) by leave-out-one method (Loo). The positive correlation of spatial descriptor Pmiz with inhibitory activity shows that proper orientation of the substitution at R position towards Z-axis is necessary to facilitate the possible interactions of the indole core with active site residues of the PLA2 enzyme. The negative contribution of b_rotN (atom and bond count-type descriptor) suggests that increasing flexibility conferred by the R substitution is detrimental for the activity. In addition to the hVPLA2 inhibitory activity is found to be highly influenced by molecular size, energy and polarity of the Me-indoxam derivatives.
authors.affiliation: Department of Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai 600 025, Tamilnadu, India.
authors.forename: G
authors.initials: G
authors.lastname: OmPraba
authors.forename: D
authors.initials: D
authors.lastname: Velmurugan
mesh_terms: D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054505:Group V Phospholipases A2; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D008956:Models, Chemical; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D010741:Phospholipases A; D054505:Group V Phospholipases A2; C516299:PLA2G5 protein, human; D054467:Phospholipases A2