Hologram quantative structure–activity relationship studies on 1-(5-carboxyindol-1-yl)propan-2-one inhibitors of human cytosolic phospholipase A2α

Abstract

A series of structurally related indole-5-carboxylic acids as potent inhibitors against human cytosolic phospholipase A2α (cPLA2α) were subjected to hologram quantative structure–activity relationship (HQSAR) analysis. A training set containing 23 compounds served to establish the HQSAR model. The best HQSAR model was generated using atoms, bond, connectivity, donor and acceptor as fragment distinction, and 3–6 as fragment size with five components showing cross-validated q 2 value of 0.790 and conventional r 2 value of 0.961. The model was then employed to predict the potency of five test set compounds that were excluded in the training set, and a good agreement between the experimental and predicted values was observed exhibiting the powerful predictable capability of this model (\( r_{\text{pred}}^{ 2} = 0. 60 5 \)). Contribution maps indicated that the carboxylic acid moiety in position 5 of the indole scaffold and the electron-withdrawing effects contributed to the inhibitory activity. Based upon some key structural features derived from HQSAR 2D contribution maps, we have designed novel inhibitors of cPLA2α possessing better inhibitory activity.