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Balasubramanian, Pavithra K.,Balupuri, Anand,Cho, Seung Joo The Basic Science Institute Chosun University 2017 조선자연과학논문집 Vol.10 No.2
Proviral Integration site of Moloney (Pim) murine Leukemia virus kinases is a serine/threonine specific protein kinase. It is largely involved in cell survival and proliferation. Pim-1 phosphorylates multiple cellular substrates to inhibit apoptosis and promote cell cycle progression. Over expression of Pim-1 kinase is observed in a range of malignancies and various solid cancers. High level of Pim-1 expression is seen in myeloma, acute myeloid leukemia, prostate cancer and liver carcinomas. Hence, Pim-1 is considered as an interesting cancer target. In the present study, we have performed region-focused CoMFA study on a series of imidazopyridazine derivatives as Pim-1 kinase inhibitors. A statistically acceptable region-focused CoMFA model ($q^2=0.571$; ONC=3; $r^2=0.909$) was developed. The model was then validated using Bootsrapping and progressive sampling. The contour map highlighted the regions favorable to increase the activity. Bulky substitutions in $R^2$ position of the phenyl ring could increase the activity. Similarly, small negative substitution in the $R^1$ position of the Pyridine ring could increase the activity considerably. Our results will be useful to design novel Pim-1 kinase inhibitors of this series.
Modelling of strains in reinforced concrete flexural members using alpha-stable distribution
K. Balaji Rao,M. B. Anoop,K. Kesavan,S. R. Balasubramanian,K. Ravisankar,Nagesh R. Iyer 사단법인 한국계산역학회 2013 Computers and Concrete, An International Journal Vol.11 No.5
Large fluctuations in surface strain at the level of steel are expected in reinforced concrete flexural members at a given stage of loading due to the emergent structure (emergence of new crack patterns). This has been identified in developing deterministic constitutive models for finite element applications in Ibrahimbegovic et al. (2010). The aim of this paper is to identify a suitable probability distribution for describing the large deviations at far from equilibrium points due to emergent structures, based on phenomenological, thermodynamic and statistical considerations. Motivated by the investigations reported by Prigogine (1978) and Rubi (2008), distributions with heavy tails (namely, alpha-stable distributions) are proposed for modeling the variations in strain in reinforced concrete flexural members to account for the large fluctuations. The applicability of alpha-stable distributions at or in the neighborhood of far from equilibrium points is examined based on the results obtained from carefully planned experimental investigations, on seven reinforced concrete flexural members. It is found that alpha-stable distribution performs better than normal distribution for modeling the observed surface strains in reinforced concrete flexural members at these points.
K. Karthick,S. Malarvizhi,V. Balasubramanian,S.A. Krishnan,G. Sasikala,Shaju K. Albert 한국원자력학회 2018 Nuclear Engineering and Technology Vol.50 No.1
Modified 9Cr-1Mo ferritic steel is a preferred material for steam generators in nuclear power plants fortheir creep strength and good corrosion resistance. Austenitic stainless steels, such as type 316LN, areused in the high temperature segments such as reactor pressure vessels and primary piping systems. So,the dissimilar joints between these materials are inevitable. In this investigation, dissimilar joints werefabricated by the Shielded Metal Arc Welding (SMAW) process with Inconel 82/182 filler metals. Thenotch tensile properties and Charpy V-notch impact toughness properties of various regions of dissimilarmetal weld joints (DMWJs) were evaluated as per the standards. The microhardness distribution acrossthe DMWJs was recorded. Microstructural features of different regions were characterized by optical andscanning electron microscopy. Inhomogeneous notch tensile properties were observed across theDMWJs. Impact toughness values of various regions of the DMWJs were slightly higher than the prescribedvalue. Formation of a carbon-enriched hard zone at the interface between the ferritic steel andthe buttering material enhanced the notch tensile properties of the heat-affected-zone (HAZ) of P91. Thecomplex microstructure developed at the interfaces of the DMWJs was the reason for inhomogeneousmechanical properties
Ligand-Based CoMFA Study on Pyridylpyrazolopyridine Derivatives as PKCθ Kinase Inhibitors
Balasubramanian, Pavithra K.,Balupuri, Anand,Cho, Seung Joo The Basic Science Institute Chosun University 2014 조선자연과학논문집 Vol.7 No.4
Protein kinase C theta (PKC-${\theta}$) is a serine/threonine specific protein kinase. It is largely expressed in the T-cells and CD28 signaling. PKC-${\theta}$ phosphorylates diverse proteins that are involved in the various cellular signaling pathways. Activated PKC-${\theta}$ in turn activates other transcription factors that control the proliferation and differentiation of T- cells. PKC-${\theta}$ is considered to be an interesting therapeutic target due to its crucial role in the proliferation, differentiation and survival of T-cells. In the present study, we have performed ligand-based CoMFA study on a series of pyridylpyrazolopyridine derivatives as PKC-${\theta}$ inhibitors. An acceptable CoMFA model ($q^2$=0.544; ONC=4; $r^2$=0.876) was developed and validated by Bootsrapping and progressive sampling. The CoMFA contour map suggested the regions to increase the activity. Bulky substitutions in R2 position of the piperizine ring could increase the activity. Similarly positive, small substitution in the R1 position of the Pyridine ring could considerably increase the activity. Our work could assist in designing more potent PKC-${\theta}$ inhibitors of pyridylpyrazolopyridine derivatives.
3D QSAR Study on Pyrrolopyrimidines-Based Derivatives as LIM2 Kinase Inhibitors
Balasubramanian, Pavithra K.,Balupuri, Anand,Cho, Seung Joo The Basic Science Institute Chosun University 2015 조선자연과학논문집 Vol.8 No.4
LIM kinases belong to the serine/Threonine kinase family. The members of the LIM kinase (LIMK) family include LIMK 1 and 2 which are involved in the regulation of actin polymerisation and microtubule disassembly. LIMK1 was shown to be involved in cancer metastasis, while LIMK2 activation promotes cells cycle progression. Since LIMK2 plays a vital role in many disease conditions such as pulmonary hypertension, cancer and viral diseases, and till date there are not much selective inhibitors been reported, LIMK2 becomes an interesting therapeutic target among the kinases. 3D QSAR study was carried out on a series of pyrrolopyrimidines based derivatives as LIMK2 inhibitors. A reasonable CoMFA ($q^2$=0.888; ONC=3; $r^2$=0.974) with good statistical values was developed. The developed model was validated using 1000 runs of boostrapping and was found to be predictable. The results of CoMFA contour map analysis suggested that the bulky substitution at $R_4$ and $R_5$ position are highly desirable to increase the activity. Similarly, positive substitution at $R_3$ position is also required to increase the activity. It is also noted that bulky substitution at $R_1$ position must be avoided. Our results could provide valuable information to enhance the activity of the LIMK2 inhibitors and to design potent pyrrolopyrimidines derivatives.
3D QSAR Studies of Mps1 (TTK) Kinase Inhibitors Based on CoMFA
Balasubramanian, Pavithra K.,Balupuri, Anand,Cho, Seung Joo The Basic Science Institute Chosun University 2016 조선자연과학논문집 Vol.9 No.2
Monopolar spindle 1 (Mps1) is an attractive cancer target due to its high expression levels in a wide range of cancer cells. Mps1 is a dual specificity kinase. It plays an essential role in mitosis. The high expression od Mps1 was observed in various grades of breast cancers. In the current study, we have developed a CoMFA model of pyridazine derivatives as Mps1 kinase inhibitors. The developed CoMFA model ($q^2=0.797$; ONC=6; $r^2=0.992$) exhibited a good predictive ability. The model was then validated by Leave out five, progressive sampling and bootstrapping and found to be robust. The analysis of the CoMFA contour maps depicted favorable and unfavorable regions to enhance the activity. Bulky positive substitution at $R^3$ position and Negative substitution in $R^1$ position is favored could increase the activity. In contrast, bulky substitution in $R^1$ position is not favored. Our results can be used in designing a potent Mps1 (TTK) inhibitor.
A CoMFA Study of Phenoxypyridine-Based JNK3 Inhibitors Using Various Partial Charge Schemes
Balasubramanian, Pavithra K.,Balupuri, Anand,Cho, Seung Joo The Basic Science Institute Chosun University 2014 조선자연과학논문집 Vol.7 No.1
The (c-Jun N-terminal kinase 3) JNK3 is a potential therapeutic target for various neurological disorders. Here, a three dimensional quantitative structure-activity relationship (3D-QSAR) study on phenoxypyridine as JNK3 inhibitors was performed to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The comparative molecular field analysis (CoMFA) using different partial atomic charges, was employed to understand the structural factors affecting JNK3 inhibitory potency. The Gasteiger-Marsili yielded a CoMFA model with cross-validated correlation coefficient ($q^2$) of 0.54 and non-cross-validated correlation coefficient ($r^2$) of 0.93 with five components. Furthermore, contour maps suggested that bulky substitution with oxygen atom in $R^3$ position could enhance the activity considerably. The work suggests that further chemical modifications of the compounds could lead to enhanced activity and could assist in the design of novel JNK3 inhibitors.
Balasubramanian, Pavithra K.,Cho, Seung Joo The Basic Science Institute Chosun University 2013 조선자연과학논문집 Vol.6 No.3
The chemokine receptor CCR1 a GPCR super family protein contains seven transmembrane domains. It plays an important role in rheumatoid arthritis, organ transplant rejection, Alzheimer's disease and also causes inflammation. Because of its role in disease processes, antagonism of CCR1 became an attractive therapeutic target. In the current study, we have taken a novel series of recently reported CCR1 antagonist of 1-(4-Phenylpiperazin-1-yl_-2-(1H-Pyrazol-1-yl) ethanone derivatives and performed a HQSAR analysis. The model was developed with Atom (A) and bond (B) parameters and with different set of atom counts to improve the model. The results of HQSAR showed good predictive ability in terms of $r^2$ (0.904) and $q^2$ (0.590) with 0.710 as standard error of prediction and 0.344 as standard error of estimate. The contribution map depicted the atom contribution in inhibitory effect. Compound-14 which was reported to be a highly active compound showed positive atom contribution in three R groups ($R^3$. $R^{5a}$ and $R^{2b}$) in inhibitory effect, which could be the reason why this compound is highly active compound whereas, the lowest active compound-6 showed negative contribution to inhibitory effect.