IKK <i>β </i> inhibitor identification: a multi-filter driven novel scaffold

Nagarajan, Shanthi,Choo, Hyunah,Cho, Yong Seo,Shin, Kye Jung,Oh, Kwang-Seok,Lee, Byung Ho,Pae, Ae Nim BioMed Central 2010 BMC bioinformatics Vol.11 No.suppl7

<P><B>Background</B></P><P>Nuclear factor kappa B (NF-κB) is a chief nuclear transcription factor that controls the transcription of various genes; and its activation is tightly controlled by Inhibitor kappa B kinase (IKK). The irregular transcription of NF-κB has been linked to auto-immune disorders, cancer and other diseases. The IKK complex is composed of three units, IKK<I>α</I>, IKK<I>β</I>, and the regulatory domain NEMO, of which IKK<I>β </I>is well understood in the canonical pathway. Therefore, the inhibition of IKK<I>β </I>by drugs forms the molecular basis for anti-inflammatory drug research.</P><P><B>Results</B></P><P>The ligand- and structure-based virtual screening (VS) technique has been applied to identify IKK<I>β </I>inhibitors from the ChemDiv database with 0.7 million compounds. Initially, a 3D-QSAR pharmacophore model has been deployed to greatly reduce the database size. Subsequently, recursive partitioning (RP) and docking filters were used to screen the pharmacophore hits. Finally, 29 compounds were selected for IKKβ enzyme inhibition assay to identify a novel small molecule inhibitor of IKK<I>β </I>protein.</P><P><B>Conclusions</B></P><P>In the present investigation, we have applied various computational models sequentially to virtually screen the ChemDiv database, and identified a small molecule that has an IC<SUB>50 </SUB>value of 20.3<I>μ</I>M. This compound is novel among the known IKK<I>β </I>inhibitors. Further optimization of the hit compound can reveal a more potent anti-inflammatory agent.</P>

3D-QSAR Studies on 2-(indol-5-yl)thiazole Derivatives as Xanthine Oxidase (XO) Inhibitors

Nagarajan, Santhosh Kumar,Madhavan, Thirumurthy The Basic Science Institute Chosun University 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 $q^2$ of 0.698 with five components and non-cross-validated correlation coefficient ($r^2$) 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 $r^2_{pred}$0.653. The CoMFA study revealed that the $R_3$ 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.

Advances in High Efficiency Back Contact Back Junction Solar Cells

Nagarajan Balaji,Cheolmin Park,Jayapal Raja,Junsin Yi 한국태양광발전학회 2015 Current Photovoltaic Research Vol.3 No.2

In the past few decade’s researchers, scientists, engineers of photovoltaic (PV) industry are working towards low cost high efficiency Si solar cells. Over the last decade the interest in back contact solar cell has been acquiring as well as a gradual introduction to industrial applications is increasing. As an alternative to conventional solar cells with a front and rear contact, the back-contact cells has remained a research topic. The aim of this work is to present a comprehensive summary of results incurred in the back contact back junction solar cells such as interdigitated back-contact (IBC), emitter wrap-through (EWT) and metallization wrap-through (MWT) over the years.

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

Nagarajan, Santhosh Kumar,Madhavan, Thirumurthy The Basic Science Institute Chosun University 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 $q^2$ of 0.607 with 6 components and $r^2$ 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 Structure Prediction of Thromboxane A2 Receptor by Homology Modeling

Nagarajan, Santhosh Kumar,Madhavan, Thirumurthy The Basic Science Institute Chosun University 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.

Purification and Characterization of a Novel Broad-spectrum Bacteriocin from Bacillus licheniformis MKU3

Nagarajan Kayalvizhi,Paramasamy Gunasekaran 한국생물공학회 2010 Biotechnology and Bioprocess Engineering Vol.15 No.2

A bacterial strain Bacillus licheniformis MKU3,isolated from slaughterhouse sediments showed a strong antimicrobial activity. The antimicrobial substance produced by this strain was found to be a protein that inhibited a broad range of bacterial strains, such as Bacillus sp.,Staphylococcus sp., Streptococcus sp., and Listeria monocytogenes. The antimicrobial peptide was purified to homogeneity by cut off membrane filtration followed by gel filtration chromatography. The purified protein with low molecular mass (< 8 kDa) was resolved as single band on Tricine SDS-PAGE. This protein was stable at 100oC for 10 min, but lost its activity at 121oC in 15 min. It was resistant to the proteolytic action of trypsin, proteinase K,and pronase E and stable within a wide range of pH (3.0~11.0). This protein exhibited lytic activity on selected indicator strain Kurthia gibsonii GCS6.

Theoretical Structure Prediction of Bradykinin Receptor B2 Using Comparative Modeling

Nagarajan, Santhosh Kumar,Madhavan, Thirumurthy The Basic Science Institute Chosun University 2016 조선자연과학논문집 Vol.9 No.4

Bradykinin receptor B2, a GPCR protein, binds with the inflammatory mediator hormone bradkynin. It plays an important role in cross-talk between the renin-angiotensin system (RAS) and the kinin-kallikrein system (KKS). Also, it is involved in many processes including vasodilation, edema, smooth muscle spasm and pain fiber stimulation. Hence, studuying the structural features of the receptor becomes important. But the unavailability of the three dimensional structure of the protein makes the analysis difficult. Hence we have performed the homology modelling of Bradykinin receptor B2 with 5 different templates. 25 different homology models were constructed. Two best models were selected based on the model validation. The developed models could be helpful in analysing the structural features of Bradykinin receptor B2 and in pathophysiology of various disorders related to them.

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

Nagarajan, Santhosh Kumar,Madhavan, Thirumurthy The Basic Science Institute Chosun University 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 $q^2$ of 0.576 with 6 components and $r^2$ 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.

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

Nagarajan, Santhosh Kumar,Madhavan, Thirumurthy The Basic Science Institute Chosun University 2016 조선자연과학논문집 Vol.9 No.2

5-hydroxytryptamine (serotonin) receptor ($5-HT_7R$) 7 is one of G-Protein coupled receptors, which is activated by the neurotransmitter Serotonin. After activation by serotonin, $5-HT_7$ activates the production of the intracellular signaling molecule cyclic AMP. $5-HT_7$ receptor has been found to be involved in the pathophysiology of various disorders. It is reported that $5-HT_7$ receptor antagonists can be used as antidepressant agents. In this study, we report the important structural and chemical parameters for 2-methoxyphenylpiperazinylakanamides as $5-HT_7R$ 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 $q^2$ of 0.594 with 6 components, $r^2$ 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 $5-HT_7R$ derivatives.

Structure Prediction of KiSS1-derived Peptide Receptor Using Comparative Modelling

Nagarajan, Santhosh Kumar,Madhavan, Thirumurthy The Basic Science Institute Chosun University 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.