HQSAR study of microsomal prostaglandin E2 synthase (mPGES-1) inhibitors

Microsomal prostaglandin E-2 synthase (mPGES-1) is an enzyme that is associated with inflammation, pain, fever and cancer. Hologram quantitative structure activity relationship (HQSAR) was conducted on the series of MK-886 compounds acting as mPGES-1 inhibitors. A training set with 24 compounds was used to establish the HQSAR model. The best model was chosen based on the cross-validated correlation coefficient (q(2) = 0.884) and the correlation coefficient (r(2) = 0.976). The model was utilized to predict the activity of the eight-test set of compounds giving the predictive r(2) value of 0.845. The descriptors of the model are based on fragment distinction (atoms, bond and connectivity) and fragment size (2-5 atoms). The atomic contribution maps generated from HQSAR were useful in identifying the important structural features responsible for the inhibitory activity of MK-886 inhibitors. Based on the generated model, the presence of hydrophobic biphenyl group seems to enhance inhibition of mPGES-1 that is in agreement with the previous experiments. In addition, it seems important for a halogen to be substituted to the biphenyl ring and for an acyl group to-be attached to the indole moiety for enhanced activity.