Send Orders of Reprints at bspsaif@emirates.net.ae 138 Medicinal Chemistry, 2013, 9, 138-151 Exploring the Biological Potential of Urea Derivatives Against mPGES-1: A Combination of Quantum Mechanics, Pharmacophore Modelling and QSAR Analyses Malkeet Singh Bahia and Om Silakari * Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India Abstract: In the present molecular modelling study, recently discovered 36 selective urea derivatives were considered to develop pharmacophore based 3D-QSAR model coupled with quantum mechanics (QM) calculations to uncover the es- sential structural features of urea molecules for mPGES-1 inhibition. The 3D-QSAR model was selected on the basis of highest values of external predictability parameters i.e. Q 2 (0.775) and Pearson-r (0.912). The model also showed the highest values of R 2 , 0.985; F-value, 306.3 and least SD, 0.147. The selected model was further validated for its external prediction power by calculating k, k  , R 2 o and R 2 o. The contour maps generated against the selected QSAR model helped to interpret the important molecular sites of urea derivatives where the suitable structural modifications would help in better complementary fit to the active site of mPGES-1, in turn would improve the potency of newly designed molecules. Keywords: Canvas, Inflammation, Jaguar, PHASE, Prostaglandin E 2 . INTRODUCTION Synthesis of prostaglandins from arachidonic acid is me- diated by the concerted action of cyclooxygenases and pros- taglandin synthases. Among all the generated prostaglandins, prostaglandin E 2 (PGE 2 ) induces various pathological condi- tions via acting through G-protein coupled receptors EP1-4 [1]. On the cellular level, prostaglandin H 2 (PGH 2 ) is con- verted into PGE 2 with the help of PGE 2 synthases. PGE 2 synthases exist in three types one cytosolic (cPGES) and two microsomal (mPGES-1 and 2) synthases. cPGES and mPGES-2 are coupled with cyclooxygenase-1 (COX-1) to release PGE 2 for homeostasis whereas mPGES-1 is coupled with cyclooxygenase-2 (COX-2) and induces the inflamma- tory PGE 2 [2,3]. In addition, the expression of inducible en- zyme mPGES-1 also gets enhanced in response to some pro- inflammatory stimuli (interleukin-1/IL-1) resulting in in- creased PGE 2 formation during inflammation [4]. This role of mPGES-1 in the release of inflammatory PGE 2 makes it an attractive target for the treatment of various disease con- ditions where PGE 2 plays a pathological role e.g. cancer, rheumatoid arthritis, pain, fever and Alzheimer disease etc [5,6]. Many researchers have also reported that mPGES-1 knockout mice show reduced occurrence of paw inflamma- tion and joint damage in rheumatoid arthritis [6,7]. Moreo- ver, unlike the therapeutic agents of other inflammatory tar gets, inhibitors of mPGES -1 do not alter the normal func- *Address correspondence to this author at the Molecular Modelling Lab (MML), Department of Pharmaceutical Sciences and Drug Research, Pun- jabi University, Patiala, 147002, Punjab India; Tel: +91 9501542696; E-mail: omsilakari@rediffmail.com tions of prostaglandins (like COX-1 inhibitors) and cardio- vascular system (like selective COX-2 inhibitors), thus the expected side effects like gastric irritation and cardiovascular system (CVS) disorders are less than those agents [8]. The present study is focused on uncovering the important structural features needed for urea derivatives to inhibit mPGES-1, with the application of atom based 3D-QSAR. Selection of training and test set molecules was done on the basis of their molecular properties in order to get the uni- form distribution of molecular data sets. The 3D structure of mPGES-1 complexed with cofactor glutathione has been solved at resolution of 3.5Å, however no complexed struc- ture is available with its inhibitor molecule [9]. Therefore, pharmacophore based alignment was preferred for the cur- rent QSAR study instead of structure and template based alignments. The best generated model was selected and vali- dated employing various statistical parameters. Finally, the best generated 3D-QSAR model can successfully be em- ployed for the designing of new congener molecules with improved potency that can further be explored as novel anti- inflammatory agents for the treatment of disorders men- tioned above. MATERIALS AND METHODS A) Selection of Dataset Molecular structures of 36 urea derivatives and their cor- responding inhibitory activities (IC 50 ) against mPGES-1 (Table 1) were collected from the published literature [10]. The IC 50 value represents the dose in micromole required to produce 50% inhibition of mPGES-1. To perform the 3D- QSAR analysis, IC 50 values were converted into correspond 7- /13 $58.00+.00 © 2013 Bentham Science Publishers