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Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2015 조선자연과학논문집 Vol.8 No.3
Corticotropin-releasing actor receptors (CRFRs) activates the hypothalamic pituitary adrenal axis, one of the 2 parts of the fight or flight response to stress. Increased CRH production has is associated with Alzheimer's disease and major depression and hypoglycemia. In this study, we report the important structural and chemical parameters for CRFR inhibitors using the derivatives of 8-substituted-2-aryl-5-alkylaminoquinolines. A 3D QSAR study, Comparative molecular field analysis (CoMFA) was performed. The best predictions were obtained for the best CoMFA model with a q2 of 0.607 with 6 components and r2 of 0.991. The statistical parameters from the generated CoMFA models indicated that the data are well fitted and have high predictive ability. The contour map resulted from the CoMFA models might be helpful in the future designing of novel and more potent CRFR derivatives.
3D-QSAR Studies on 2-(indol-5-yl)thiazole Derivatives as Xanthine Oxidase (XO) Inhibitors
Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2015 조선자연과학논문집 Vol.8 No.4
Xanthine Oxidase is an enzyme, which oxidizes hypoxanthine to xanthine, and xanthine to uric acid. It is widely distributed throughout various organs including the liver, gut, lung, kidney, heart, brain and plasma. It is involved in gout pathogenesis. In this study, we have performed Comparative Molecular Field Analysis (CoMFA) on a series of 2-(indol- 5-yl) thiazole derivatives as xanthine oxidase (XO) inhibitors to identify the structural variations with their inhibitory activities. Ligand based CoMFA models were generated based on atom-by-atom matching alignment. In atom-by-atom matching, the bioactive conformation of highly active molecule 11 was generated using systematic search. Compounds were aligned using the bioactive conformation and it is used for model generation. Different CoMFA models were generated using different alignments and the best model yielded a cross-validated q2 of 0.698 with five components and non-cross-validated correlation coefficient (r2) of 0.992 with Fisher value as 236.431, and an estimated standard error of 0.068. The predictive ability of the best CoMFA models was found to be r2 pred 0.653. The CoMFA study revealed that the R3 position of the structure is important in influencing the biological activity of the inhibitors. Electro positive groups and bulkier substituents in this position enhance the biological activity.
3D Structure Prediction of Thromboxane A2 Receptor by Homology Modeling
Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2015 조선자연과학논문집 Vol.8 No.1
Thromboxane A2 receptors (TXA2-R) are the G protein coupled receptors localized on cell membranes and intracellular structures and play pathophysiological role in various thrombosis/hemostasis, modulation of the immune response, acute myocardial infarction, inflammatory lung disease, hypertension and nephrotic disease. TXA2 receptor antagonists have been evaluated as potential therapeutic agents for asthma, thrombosis and hypertension. The role of TXA2 in wide spectrum of diseases makes this as an important drug target. Hence in the present study, homology modeling of TXA2 receptor was performed using the crystal structure of squid rhodopsin and night blindness causing G90D rhodopsin. 20 models were generated using single and multiple templates based approaches and the best model was selected based on the validation result. We found that multiple template based approach have given better accuracy. The generated structures can be used in future for further binding site and docking analysis.