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|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 PLA₂ (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.|
|Appears in Collections:||IJBB Vol.43(3) [June 2006]|
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