Here we report the results of the application of a quantum-chemical model-based method to the uncovering of the electronic factors controlling the variation of the inhibitory activity of microsomal prostaglandin E2 synthase-1 by 2-aryl substituted quinazolin-4(3H)-one, pyrido[4,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4(3H)-one derivatives. The electronic structure was calculated at the B3LYP/6-31G(d,p) level. Complementary docking studies were carried out with a crystal structure of human mPGES-1. We found a good relationship between the electronic structures and inhibitory activities and a partial pharmacophore was proposed. Our results suggest specific interactions between some atoms and unknown residues of the enzyme. Docking studies show what residues are available for these specific interactions.
