Send Orders of Reprints at reprints@benthamscience.net Combinatorial Chemistry & High Throughput Screening, 2013, 16, 249-273 249 1875-5402/13 $58.00+.00 © 2013 Bentham Science Publishers 3D QSAR and Docking Study of Gliptin Derivatives as DPP-IV Inhibitors Ritesh Agrawal *,1 , Pratima Jain 1 , Subodh Narayan Dikshit 1 and Radhe Shyam Bahare 2 1 Department of Chemistry, Shrimant Madhavrao Scindia, Government Model Science College, Jhansi Road, Gwalior, Madhya Pradesh, PIN No. 474001, India 2 Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra Ranchi, Jharkhand, PIN No. 835215, India Abstract: The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 46 xanthine derivatives reported for DPP-IV inhibition using PHASE module of Schrodinger software. The present works also encompasses molecular interaction of 46 xanthine ligand through maestro 8.5 software. The QSAR study comprises AHHR.7 pharmacophore hypothesis, which elaborates the three points, e.g. one hydrogen bond acceptor (A), two hydrophobic rings (H) and one aromatic ring (R). The discrete geometries as pharmacophoric feature were developed and the generated pharmacophore model was used to derive a predictive atom- based 3D QSAR model for the studied data set. The obtained 3D QSAR model has an excellent correlation coefficient value (r 2 = 0.9995) along with good statistical significance which is indicated by high Fisher ratio (F= 8537.4). The model also exhibits good predictive power confirmed by the high value of cross validated correlation coefficient (q 2 = 0.6919). The QSAR model suggests that hydrophobic character is crucial for the DPP-IV inhibitory activity exhibited by these compounds and inclusion of hydrophobic substituents will enhance the DPP-IV inhibition. In addition to the hydrophobic character, electron withdrawing groups positively contribute to the DPP-IV inhibition potency. The findings of the QSAR study provide a set of guidelines for designing compounds with better DPP-IV inhibitory potency. Keywords: DPP-IV inhibitors, docking, maestro, pharmacophore, PHASE, QSAR, Schrödinger. INTRODUCTION The three dimensional quantitative structure activity relationship (3D QSAR) analysis involves the quantitative relationship between the biological activity of a set of compounds and their three dimensional structural properties, using statistical correlation methods. Three dimensional QSAR approach is one of the most powerful techniques, which falls in the class of indirect drug design, thus lead optimization without receptor 3D structure is one of the most important applications of 3D QSAR. It allows visual interpretation of spatial arrangement of structural features with biological activity, which is advantageous over 2D QSAR. Type II Diabetes is a major cause of morbidity and mortality in the industrialized world. The cardiovascular diseases are leading cause of mortality. The number of Type II diabetes patients is increasing rapidly and the number of patients is expected to reach between 300 and 380 million by 2025, thereby placing an enormous economic burden on global healthcare has been noticed. The worldwide epidemic of Type II Diabetes (NIDDM) has been stimulating the search for new concepts and targets for the treatment of Type II Diabetes incurable disease. Most current therapies were developed in the absence of defined molecular targets. Increasing knowledge on the biochemical and cellular alterations occurring in NIDDM, which lead to the *Address correspondence to this author at the Department of Chemistry, Shrimant Madhavrao Scindia, Government Model Science College, Jhansi Road, Gwalior, Madhya Pradesh, PIN No. 474001, India; Tel: 0751- 2323649, 4014438; E-mail: riteshagrawalip@gmail.com development of novel and potentially more effective therapeutic approaches to cure the disease. Novel emerging targets for Type-II diabetes include Dipeptidyl peptidase-IV enzyme. The role of Dipeptidyl peptidase-IV enzyme in the regulation of lipid metabolism, insulin and triglycerides leads to the rational design of several Dipeptidyl peptidase- IV inhibitors [1]. DPP-IV selectively cleaves two amino acids from peptides, such as GLP-1 and GIP, which have proline or alanine in the second position. At the active site of the protease, there is a characteristic motif of three amino acids, Asp-His-Ser. Dipeptidyl peptidase-IV inhibitors, which are formally known as Gliptins. Table 1 summarized various approved gliptins from the regulatory agencies, e.g. USFDA, EMEA, Japan FDA and India. The Gliptins were used as a reference for docking studies in the present work. With a view of progression of this DPP-IV class of inhibitors and our continuing interest in the development of DPP-IV inhibitors, a quantitative structure activity relationship analysis was proposed on the series of xanthine derivatives reported for DPP-IV inhibitory activity by Frank Himmelsbach et al. [4]. The xanthine derivatives have been studied in the same lab with respect to environmental changes errors. In order to establish the relationship between the spatial three dimensional pharmacophoric features and DPP-IV activity of a group of xanthine derivatives. A three- dimensional QSAR analysis was carried out on the combined dataset employing PHASE module of molecular modeling software Schrodinger.