Research Article MOLECULAR DOCKING STUDIES ON SELECTED PHYTOCOMPOUNDS FROM DIFFERENT Andrographis sp AGAINST PPAR-γ and C/EBP-α RECEPTORS FOR TYPE-2-DIABETES V.SUDARSHANA DEEPA 1* , P. SURESH KUMAR 2 , B.VADIVUKKARASI 3 AND FLORIDA TILTON 4 1 Department of Biotechnology, Bannari Amman Institute of Technology (Autonomous), Sathyamangalam-638401, Erode (Dt), 2 Department of Biotechnology, Anna University Chennai, BIT campus, Tiruchirappalli-620024, 3 Department of Bioinformatics, Biozone Research Technologies, Pvt.Limited, Chennai-600018, 4 Managing Director, Biozone Research Technologies, Pvt.Limited, Chennai- 600018, E-mail:sudarshanadeepa@gmail.com Received: 21 March 2013, Revised and Accepted: 1 April 2013 ABSTRACT Diabetes mellitus is a prevalent disease affecting the citizens of both developed and developing countries. Despite considerable progress in the treatment of diabetes by oral hypoglycemic agents, search for newer drugs continues because the existing synthetic drugs have several limitations. The herbal drugs with antidiabetic activity are yet to be commercially formulated as modern medicines, even though they have been acclaimed for their therapeutic properties in the traditional systems of medicine. The present work deals with the analysis of binding mechanism of 11 selected natural compounds from different Andrographis species against the novel targets for type T2D namely C/EBP-Ƚ and PPAR-ɀ compared with Rosiglitazone (standard compound) using GOLD software. The results revealed that most of the selected herbal lead compounds were effective targets against the receptors. These compounds showed favorable interactions with the amino acid residues thereby substantiating their proven efficacy as anti-diabetic compounds. The resulting data of receptor-ligand interactions demonstrates that in silico screening method is highly efficient for identifying potential lead compounds against major disorders/diseases. Keywords: PPAR-ɀ,C/EBP-Ƚ,Andrographis sp,type 2 diabetes,,3T3-L1 cells INTRODUCTION Type 2 diabetes (T2D) poses a major health problem globally, especially in many developing countries 1 .It is brought about when the cells in the muscles, liver, and fat tissues fail to utilize insulin effectively. Human body has to maintain the blood glucose level at a very narrow range, which is done with insulin and glucagon 2 . The function of glucagon is causing the liver to release glucose from its cells into the blood, for the production of energy. The worldwide prevalence of diabetes for all age groups was estimated to be 2.8% in 2000 and it is projected to be 5.4% in 2025 3 . Currently available therapies for T2D include antidiabetic agents such as sulfonylureas, biguanides, Ƚ-glucosidase inhibitors and thiazolidindione .Due to the side effects associated with the oral hypoglycemic agents there is a growing interest in herbal remedies 4 . Carbohydrate metabolism and differentiation of 3T3-L1 adipocytes are associated with diabetes. Peroxisome proliferators activated receptor gamma (PPAR-ɀȌ and the CCAAT/enhancer binding protein family (C/EBP-Ƚ, Ⱦ, and ɁȌ are critical factors in ͵T͵-L1preadipocyte differentiation 5 . There has been an extensive research focused on PPAR-ɀ belonging to nuclear receptor family and C/EBP-Ƚ CAAT enhancer binding proteins which are ligand-activated transcription factors. PPAR-ɀ and C/EBP-Ƚ is expressed most abundantly in adipose tissue and mediates the antidiabetic activity of the insulin- sensitizing drugs belonging to the thiazolidindione 6 . This key transcriptional factor plays a pivotal role in regulating adipogenesis, insulin sensitivity and glucose homeostasis 7 . A drug molecule is triggered when the binding of small molecule to the receptor protein is perfectly done. Such protein-ligand interaction is comparable to the lock-and-key principle, in which the lock encodes the protein and the key is ensembled with the ligand. The major driving force for binding appears to be hydrophobic interaction whose specificity is however controlled by hydrogen bonding interactions 8 . Therefore, in the present study the species Andrographis is said to have antidiabetic property 9 .Hence phytocompounds from this species were selected and further investigated for its binding efficiency to evaluate the best fit molecule using GOLD (Genetic Optimization of Ligand Docking). MATERIALS AND METHODS Structure of PPAR-γ The X-Ray crystallographic structure of PPAR-ɀ was obtained from the Protein Data Bank (PDB). The PDB ID 3DZY corresponds to the crystal structure of the receptor. The structure of PPAR-ɀ is composed of six polypeptides chains with 467 amino acids. We have employed the GOLD software to screen the activity of the 13 compounds against the receptor 3DZY. The consensus scoring and ranking was used to determine the results of Molecular screening (Figure: 1). Figure 1: 3D structure of PPAR-γ Structure of C/EBP-α The C/EBP-Ƚ protein sequence was retrieved from the NCB) protein database and the corresponding three dimensional structures were not resolved experimentally in the PDB database. Hence MODELLER 9.10 was used to predict the three dimensional structure of human C/EBP-Ƚ Α with Mouse C/EBP-Ƚ Α as the template ȋPDB )D ͳNWQ with a resolution of 2.80 Angstroms). The Ramachandran plot evaluation using PROCHECK shows that the structure has 92.7% of residues in the core region, thus proving a stable model. This model was taken further for docking studies (Figure: 2). Asian Journal of Pharmaceutical and Clinical Research Vol 6, Suppl 2, 2013 ISSN - 0974-2441 Academic Sciences