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3D QSAR Study of Human PLA2 Inhibitors. A Modeling Approach to Select New and Specific Anti-Inflammatory Drugs

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High concentrations of human non pancreatic secretory phospholipase A2 (hnps-PLA2) have been reported as inducing factors in different inflammatory diseases. Thus, hnps-PLA2 inhibitors would be potential drugs against disorders generated by high levels of this enzyme. The latter has been crystallized with different ligands and several classes of inhibitors are known, but the optimization of their therapeutic properties requires: (i) a better understanding of the inhibitorprotein interaction mechanism, and (ii) finding a strategy to predict the activity of new molecules. Approaches related to computational chemistry may help to resolve these two problems.

An automated docking study was performed on a series of 188 competitive hnps-PLA2 inhibitors. The docking data were then used to establish 3D QSAR models by combining Comparative Molecular Field Analysis (CoMFA) and PLS modeling. The robustness and prediction power of the best model were assessed with help of cross-validation and test set procedures that delivered excellent scores. The search for the best inhibitors against hnps-PLA2 has to be associated with a high specificity of the molecules selected, minimizing possible human side effects. This requires keeping at an extremely low level the inhibitor's activity against human pancreatic phospholipase A2 (hp-PLA2) which is in negligible concentration in all tissues except in pancreatic ones. Then, the above mentioned modeling procedure was applied also on a series of hp-PLA2 inhibitors and, once more, the 3D QSAR model thus generated showed an excellent robustness and prediction power.

Finally, the combination of the two models generated on hnps-PLA2 and hp-PLA2 offered a global predictive tool able to select new strong anti-inflammatory drugs with negligible side effects, at least at pancreatic level.

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Keywords: 3D QSAR; CoMFA; PLS; Phospolipase A2; automated docking

Document Type: Research Article

Affiliations: BioChemics Consulting, 16 rue Leonard de Vinci, 45074 Orleans, France.

Publication date: 2006-05-01

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  • Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new Anti-Inflammatory & Anti-Allergy Agents.

    Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics in Anti-Inflammatory & Anti-Allergy Medicinal Chemistry.

    Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in Anti-Inflammatory & Anti-Allergy Agents drug discovery.
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