Protein Phosphatase 1D (PPM1D) Structure Prediction Using Homology Modeling

Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2016 조선자연과학논문집 Vol.9 No.1

Protein phosphatase manganese dependent 1D (PPM1D) is one of the Ser/Thr protein phosphatases belongs to the PP2C family. They play an important role in cancer tumorigenesis of various tumors including neuroblastoma, pancreatic adenocarcinoma, medulloblastoma, breast cancer, prostate cancer and ovarian cancer. Even though PPM1D is involved in the pathophysiology of various tumors, the three dimensional protein structure is still unknown. Hence in the present study, homology modelling of PPM1D was performed. 20 different models were modelled using single- and multipletemplate based homology modelling and validated using different techniques. Best models were selected based on the validation. Three models were selected and found to have similar structures. The predicted models may be useful as a tool in studying the pathophysiological role of PPM1D.

Comparative Molecular Similarity Indices Analysis (CoMSIA) of 8-substituted-2-aryl-5-alkylaminoquinolines as Corticotropin-releasing factor-1 Receptor Antagonists

Santhosh Kumar Nagarajan and Thirumurthy Madhavan 조선대학교 기초과학연구원 2016 조선자연과학논문집 Vol.9 No.4

Corticotropin-releasing factor receptors (CRFRs) activate the hypothalamic-pituitary-adrenal axis, which is an integral part of the fight or flight response to stress. Increase in CRH level is observed in Alzheimer’s disease and major depression and hypoglycemia. Here, we report on the relevant physicochemical parameters required for the CRFR inhibitors. Comparative molecular similarity indices analysis (CoMSIA) was performed with the derivatives of 8-substituted-2-aryl-5-alkylaminoquinolinesas CRFR inhibitors. The best predictions were obtained for the best CoMSIA model with a q2 of 0.576 with 6 components and r2 of 0.977. The statistical parameters from the generated CoMSIA models indicated that the data are well fitted and have high predictive ability. CoMSIA contour maps could be useful in the designing of more potent and novel CRFR derivatives. Keywords: 3D-QSAR, CoMSIA, CRFR, CRHR

Binding Interaction Analysis of Neuromedin U Receptor 1 with the Native Protein Neuromedin U

Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2017 조선자연과학논문집 Vol.10 No.1

Neuromedin, a neuropeptide, which is involved in various functions that include contractile activity on smooth muscle, controlling the blood flow and ion transport in the intestine, increased blood pressure and regulation of adrenocortical function. It is involved in the pathophysiology of various immune mediated inflammatory diseases like asthma. In this study, we have performed protein-protein docking analysis of neuromedin U – neuromedin U receptor 1 complex. We have developed homology models of neuromedin U, and selected a reliable model using model validation. The model was docked with the receptor model, to analyse the crucial interactions of the complex. This study could be helpful as a tool in developing novel and potent drugs for the diseases related with neuromedin U receptor 1.

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.

Three Dimensional Structure Prediction of Neuromedin U Receptor 1 Using Homology Modelling

Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2017 조선자연과학논문집 Vol.10 No.1

Neuromedin U receptor 1 is a GPCR protein which binds with the neuropeptide, neuromedin. It is involved in the regulation of feeding and energy homeostasis and related with immune mediated inflammatory diseases like asthma. It plays an important role in maintaining the biological clock and in the regulation of smooth muscle contraction in the gastrointestinal and genitourinary tract. Analysing the structural features of the receptor is crucial in studying the pathophysiology of the diseases related to the receptor important. As the three dimensional structure of the protein is not available, in this study, we have performed the homology modelling of the receptor using 5 different templates. The models were subjected to model validation and two models were selected as optimal. These models could be helpful in analysing the structural features of neuromedin U receptor 1 and their role in disorders related to them.

3D-QSAR Studies of 8-Substituted-2-aryl-5-alkylaminoquinolines as Corticotropin-releasing Factor-1 Receptor Antagonists

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.

Comparative Molecular Similarity Index Analysis on 2-(indol-5-yl)thiazolederivatives as Xanthine Oxidase(XO)inhibitors

Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2016 조선자연과학논문집 Vol.9 No.3

Xanthine Oxidase is an enzyme, which oxidizes hypoxanthine to xanthine, and xanthine to uric acid. It is widely distributed throughout various organsincluding 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 (CoMSIA) 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 CoMSIA 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 CoMSIA models were generated using different alignments and the best model yielded across- 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 CoMSIA models was found to be r2 pred 0.653. The study revealed the important structural features required for the biological activity of the inhibitors and could provide useful for the designing of novel and potent drugs for the inhibition of Xanthine oxidase

3D QSAR Study of 2-Methoxyphenylpiperazinylakanamides as 5-Hydroxytryptamine (Serotonin) Receptor 7 Antagonists

Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2016 조선자연과학논문집 Vol.9 No.2

5-hydroxytryptamine (serotonin) receptor (5-HT7R) 7 is one of G-Protein coupled receptors, which is activated by the neurotransmitter Serotonin. After activation by serotonin, 5-HT7 activates the production of the intracellular signaling molecule cyclic AMP. 5-HT7 receptor has been found to be involved in the pathophysiology of various disorders. It is reported that 5-HT7 receptor antagonists can be used as antidepressant agents. In this study, we report the important structural and chemical parameters for 2-methoxyphenylpiperazinylakanamides as 5-HT7R inhibitors. A 3D QSAR study based on comparative molecular field analysis (CoMFA) was performed. The best predictions were obtained for the best CoMFA model with q2 of 0.594 with 6 components, r2 of 0.986, Fisher value as 60.607, and an estimated standard error of 0.043. The predictive ability of the test set was 0.602. Results obtained the CoMFA models suggest that the data are well fitted and have high predictive ability. The contour maps are generated and studied. The contour analyses may serve as tool in the future for designing of novel and more potent 5-HT7R derivatives.

Structure Prediction of KiSS1-derived Peptide Receptor Using Comparative Modelling

Santhosh Kumar Nagarajan, Thirumurthy Madhavan 조선대학교 기초과학연구원 2016 조선자연과학논문집 Vol.9 No.2

KiSS1-derived peptide receptor, a GPCR protein, binds with the hormone kiss peptin. They are important in the neuroendocrine regulation of reproduction and in the secretion of gonadotrophin-releasing hormone. Thus, analysing the structural features of the receptor becomes important. However, the three dimensional structure of the protein is unavailable. Hence in this study, we have performed the homology modelling of KiSS1-derived peptide receptor with 5 different templates. 30 models were constructed using two platforms – Easymodeller and ITasser. The optimal models were chosen based on the model validation. Two models were selected after validation. The developed models could provide useful for analysing the structural features of KiSS1-derived peptide receptor and their pathophysiological role in various disorders related to them.