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Rama Rao K.V.S.N.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Battula S.K.,MLR Institute of Technology
Advances in Intelligent Systems and Computing | Year: 2015

IDS is a powerful tool in monitoring intruders. It detects the intruders based on pre defined patterns known as signatures. But in the context of an enterprise, a single IDS for the whole organization may not function effectively as there will be several business units (domains) such as HR, Finance, Marketing etc. Each business unit will have its own set of activities, business rules and security requirements. It should be possible for the personnel in these enterprise business units to enter their own security business rules. Since many of these personnel do not have expertise in writing signature to IDS, it would be convenient for them to specify the rules in Natural Language statements like English. These natural language statements should be converted to IDS signatures and are supposed to be added to signature database. In this paper, we have provided an interface to enter rules in natural language. Using Sentimental Analysis technique, we processed the natural language statements for conversion to IDS signatures. The converted signatures are added to corresponding business domain signature database. These domain specific customized signatures will certainly enhance the security of an enterprise. © Springer India 2015.

Kavita Kumari K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Setty O.H.,University of Hyderabad
Journal of Cancer Science and Therapy | Year: 2012

Background: The combination of mitomycin C and cisplatin was proved to be beneficial in the treatment of lung cancer, breast cancer, anal carcinoma and human cervical cancer treatment. However, dose related toxicity happens to be one of the major concerns the treatment, leading to its discontinuation, although the patient's response is encouraging. The aim of the present investigation was to study the protective effects of Berberis aristata (10 mg/kg body weight) on the mitochondrial dysfunction caused due to administration of mitomycin C (2 mg/kg body wt, i.p) and cisplatin (12 mg/kg body wt, i.p). Methods: We have investigated the effects and protective effects on oxidative phosphorylation enzymes, of the electron transport system, lipid peroxidation and phospholipid composition in liver and kidney mitochondria. Results: Co-administration of mitomycin C and cisplatin resulted in significant decrease in active respiration (State 3 Respiration), Respiratory Control Ratio (RCR) and P/O ratio's using either succinate or glutamate plus malate as substrate. Altered enzyme activities of NADH dehydrogenase, succinate dehydrogenase, succinate- cytochrome c reductase, NADH-cytochrome c reductase, cytochrome c oxidase was observed. The level of lipid peroxides was increased, and with a significant decrease in phospholipid content. Prior administration of Berberis aristata protected against observed mitochondrial dysfunction. Conclusions: We believe that prior administration of Berberis aristata could reduce the damage to mitochondrial function, by scavenging free radicals and thereby, preventing uncoupling of oxidative phosphorylation, deactivation of enzymes of electron transport chain, generation of lipid peroxides, oxidation of phospholipids ultimately inhibiting the signaling wave propagation to the mitochondria death receptor (membrane bound cytochrome c), which generally leads to apoptosis. © 2012 Kavita Kumari K, et al.

Kakarala K.K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Jamil K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS
Molecular Phylogenetics and Evolution | Year: 2014

Current methods of G protein coupled receptors (GPCRs) phylogenetic classification are sequence based and therefore inappropriate for highly divergent sequences, sharing low sequence identity. In this study, sequence structure profile based alignment generated by PROMALS3D was used to understand the GPCR Class A Rhodopsin superfamily evolution using the MEGA 5 software. Phylogenetic analysis included a combination of Neighbor-Joining method and Maximum Likelihood method, with 1000 bootstrap replicates. Our study was able to identify potential ligand association for Class A Orphans and putative/unclassified Class A receptors with no cognate ligand information: GPR21 and GPR52 with fatty acids; GPR75 with Neuropeptide Y; GPR82, GPR18, GPR141 with N-arachidonylglycine GPR176 with Free fatty acids, GPR10 with Tachykinin & Neuropeptide Y; GPR85 with ATP, ADP & UDP glucose; GPR151 with Galanin; GPR153 and GPR162 with Adrenalin, Noradrenalin; GPR146, GPR139, GPR142 with Neuromedin, Ghrelin, Neuromedin U-25 & Thyrotropin-releasing hormone GPR171 with ATP, ADP & UDP Glucose; GPR88, GPR135, GPR161, GPR101with 11-cis-retinal; GPR83 with Tackykinin; GPR148 with Prostanoids, GPR109b, GPR81, GPR31with ATP & UTP and GPR150 with GnRH I & GnRHII. Furthermore, we suggest that this study would prove useful in re-classification of receptors, selecting templates for homology modeling and identifying ligands which may show cross reactivity with other GPCRs as signaling via multiple ligands play a significant role in disease modulation. © 2014 Elsevier Inc.

Kakarala K.K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Jamil K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS
Journal of Receptors and Signal Transduction | Year: 2015

Context: Drug resistance and drug-associated toxicity are the primary causes for withdrawal of many drugs, although patient recovery is satisfactory in many instances. Interestingly, the use of phytochemicals in the treatment of cancer as an alternative to synthetic drugs comes with a host of advantages; minimum side effects, good human absorption and low toxicity to normal cells. Protease activated receptor 1 (PAR1) has been established as a promising target in many diseases including various cancers. Strong evidences suggest its role in metastasis also. Objective: There are no natural compounds known to inhibit its activity, so we aimed to identify phytochemicals with antagonist activity against PAR1. Methods: We screened phytochemicals from Naturally Occurring Plant-based Anticancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/) against PAR1 using virtual screening workflow of Schrödinger software. It analyzes pharmaceutically relevant properties using Qikprop and calculates binding energy using Glide at three accuracy levels (high-throughput virtual screening, standard precision and extra precision). Results and conclusion: Our study led to the identification of phytochemicals, which showed interaction with at least one experimentally determined active site residue of PAR1, showed no violations to Lipinski's rule of five along with predicted high human absorption. Furthermore, structural interaction fingerprint analysis indicated that the residues H255, D256, E260, S344, V257, L258, L262, Y337 and S344 may play an important role in the hydrogen bond interactions of the phytochemicals screened. Of these residues, H255 and L258 residues were experimentally proved to be important for antagonist binding. The residues Y183, L237, L258, L262, F271, L332, L333, Y337, L340, A349, Y350, A352, and Y353 showed maximum hydrophobic interactions with the phytochemicals screened. The results of this work suggest that phytochemicals Reissantins D, 24,25-dihydro-27-desoxywithaferin A, Isoguaiacin, 20-hydroxy-12-deoxyphorbol angelate, etc. could be potential antagonist of PAR1. However, further experimental studies are necessary to validate their antagonistic activity against PAR1. © 2014 Informa Healthcare USA, Inc. All rights reserved.

Kumari K.K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Setty O.H.,University of Hyderabad
Journal of Bioenergetics and Biomembranes | Year: 2012

The evolving role of mitochondria, in mediating chemotherapy-induced apoptosis motivated us for the studies described here. The combination of cisplatin and cyclophosphamide is widely used in treating various types of cancers. The purpose of our study was to understand the mechanism of the toxicity induced by the co-administration of cisplatin and cyclophosphamide, on mitochondrial bioenergetics, and to study the protective effect of prior administration of the medicinal plant extract Phyllanthus fraternus. Our results reveal that co-administration of cisplatin (12 mg/kg, i.p) and cyclophosphamide (150 mg/kg, oral) to wistar rats (100 g) significantly alters mitochondrial structure and hence function. The rate of mitochondrial respiration was decreased significantly with both NAD + and FAD-linked substrates. The respiratory control ratio, an index of membrane integrity and the P/O ratio, a measure of phosphorylating efficiency also were decreased significantly accompanied by elevation in the lipid peroxide levels in liver, kidney homogenate and liver mitochondria respectively. Also, the phospholipid content of the mitochondrial membrane, showed a significant decrease, indicating mitochondrial membrane changes. Prior administration of an aqueous extract of P. fraternus (100 mg/kg) to rats, showed protection on all parameters investigated. Administration of P. fraternus alone did not show any significant changes on mitochondrial membrane bioenergetics. Thus, we propose, that the toxic side effects of cisplatin + cyclophosphamide, are due to a chain of interconnected events, within the mitochondrial inner membrane, ultimately leading to hepatotoxicity and nephrotoxicity. Further, our work also suggests that administration of aqueous extract of P. fraternus can enhance the therapeutic potential of anticancer drugs by reducing drug related toxicity. © 2012 Springer Science+Business Media, LLC.

Shaik A.P.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Shaik A.P.,King Saud University | Bammidi V.K.,Burton | Sampathirao K.,Burton | Jamil K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS
Journal of Obstetrics and Gynaecology | Year: 2011

A meta-analyses of endothelial nitric oxide synthase (eNOS) and angiotensin-converting enzyme (ACE) gene polymorphisms in pre-eclampsia was performed. We shortlisted 33 studies (17 for ACE; 16 for eNOS gene polymorphisms), of which 29 articles (16 for ACE and 15 for eNOS) were analysed. Overall, 1,620 cases with pre-eclampsia and 2,158 controls were analysed for intron 16 insertiondeletion polymorphism in ACE gene. A total of 1,610 subjects with pre-eclampsia and 2,875 controls were analysed for the Glu298Asp in eNOS gene. Overall, the random-effects odds ratio (OR) with Glu298Asp in eNOS gene was 0.958 (95% confidence intervals, CI 0.747-1.228, p > 0.05), and for the insertiondeletion/ACE polymorphism was 0.987 (95% CI 0.6981.395, p > 0.05). Significant heterogeneity was observed in the studies that evaluated polymorphisms in ACE (Q value = 55.6; I 2 = 73; p value = 0.000); and eNOS (Q value = 37.2; I 2 = 62.4; p value = 0.001) polymorphisms. No significant risk of pre-eclampsia was observed in both eNOS and ACE genes with these polymorphisms. © 2011 Informa UK, Ltd.

Kakarala K.K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Jamil K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Devaraji V.,JKK Nataraja Dental College and Hospital
Journal of Molecular Graphics and Modelling | Year: 2014

Experimental evidences have observed enhanced expression of protease activated receptor 2 (PAR2) in breast cancer consistently. However, it is not yet recognized as an important therapeutic target for breast cancer as the primary molecular mechanisms of its activation are not yet well-defined. Nevertheless, recent reports on the mechanism of GPCR activation and signaling have given new insights to GPCR functioning. In the light of these details, we attempted to understand PAR2 structure & function using molecular modeling techniques. In this work, we generated averaged representative stable models of PAR2, using protease activated receptor 1 (PAR1) as a template and selected conformation based on their binding affinity with PAR2 specific agonist, GB110. Further, the selected model was used for studying the binding affinity of putative ligands. The selected ligands were based on a recent publication on phylogenetic analysis of Class A rhodopsin family of GPCRs. This study reports putative ligands, their interacting residues, binding affinity and molecular dynamics simulation studies on PAR2-ligand complexes. The results reported from this study would be useful for researchers and academicians to investigate PAR2 function as its physiological role is still hypothetical. Further, this information may provide a novel therapeutic scheme to manage breast cancer. © 2014 Elsevier Inc.

Subhani S.,Bhagwan Mahavir Medical Research Center and 10 1 1 | Jayaraman A.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Jamil K.,Bhagwan Mahavir Medical Research Center and 10 1 1 | Jamil K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS
Biomedicine and Pharmacotherapy | Year: 2015

MDR1, a protein commonly involved in drug transport, has been linked to multi drug resistance and disease progression in cancers such as non-small cell lung cancer. Hence, targeting this protein is essential for improving drug design and preventing adverse drug-drug interactions. The aim of the study was to examine chemotherapeutic drug binding to MDR1 and the interactions therein. We have used Schrödinger suite 2014, to perform homology modelling of human MDR1 based on Mouse MDR1, followed by Induced Fit Docking with Paclitaxel, Docetaxel, Gemcitabine, Carboplatin and Cisplatin drugs. Finally, we evaluated drug binding affinities using Prime/MMGBSA and using these scores we compared the affinities of combination therapies against MDR1. Analysis of the docking results showed Paclitaxel > Docetaxel > Gemcitabine > Carboplatin > Cisplatin as the order of binding affinities, with Paclitaxel having the best docking score. The combination drug binding affinity analysis showed Paclitaxel + Gemcitabine to have the best docking score and hence, efficacy. Through our investigation we have identified the residues Gln 195 and Gln 946 to be more frequently involved in drug binding interactions with MDR1. Our results suggest that, Paclitaxel or combination of Paclitaxel + Gemcitabine could serve as a suitable therapy against MDR1 in NSCLC patients. Thus, our study provides new insight into the possible repurposing of chemotherapeutic drugs in targeting elevated MDR1 levels in NSCLC patients, thereby ensuring better overall outcome. Further our study highlights the use of in silico methodologies in understanding drug binding to protein targets and its relevance to advancing lung cancer therapy. © 2015 Elsevier Masson SAS.

Kakarala K.K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Jamil K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS
Journal of Biomolecular Structure and Dynamics | Year: 2015

Protease activated receptor 2 (PAR2) has emerged as one of the promising therapeutic targets to inhibit rapidly metastasizing breast cancer cells. However, its elusive molecular mechanism of activation and signaling has made it a difficult target for drug develoment. In this study, in silico methods were used to unfold PAR2 molecular mechanism of signaling based on the concept of GPCR receptor plasticity. Although, there are no conclusive evidences of the presence of specific endogenous ligands for PAR2, the efficacy of synthetic agonist and antagonist in PAR2 signaling has opened up the possibilities of ligand-mediated signaling. Furthermore, it has been proved that ligands specific for one GPCR can induce signaling in GPCRs belonging to other subfamilies. Therefore, the aim of this study was to identify potential agonists and antagonists from the GPCR ligand library (GLL), which may induce biased signaling in PAR2 using the concept of existence of multiple ligand-stabilized receptor conformations. The results of our in silico study suggest that PAR2 may show biased signaling mainly with agonists of serotonin type 1, β-adrenergic type 1,3 and antagonists of substance K (NK1), serotonin type 2, dopamine type 4, and thromboxane receptors. Further, this study also throws light on the putative ligand-specific conformations of PAR2. Thus, the results of this study provide structural insights to putative conformations of PAR2 and also gives initial clues to medicinal chemists for rational drug design targeting this challenging receptor. © 2015 Taylor & Francis.

Kakarala K.K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS | Jamil K.,Jawaharlal Nehru Institute of Advanced Studies JNIAS
Journal of Biomolecular Structure and Dynamics | Year: 2015

The use of phytochemicals either singly or in combination with other anticancer drugs comes with an advantage of less toxicity and minimal side effects. Signaling pathways play central role in cell cycle, cell growth, metabolism, etc. Thus, the identification of phytochemicals with promising antagonistic effect on the receptor/s playing key role in single transduction may have better therapeutic application. With this background, phytochemicals were screened against protease-activated receptor 2 (PAR2). PAR2 belongs to the superfamily of GPCRs and is an important target for breast cancer. Using in silico methods, this study was able to identify the phytochemicals with promising binding affinity suggesting their therapeutic potential in the treatment of breast cancer. The findings from this study acquires importance as the information on the possible agonists and antagonists of PAR2 is limited due its unique mechanism of activation. © 2014 Taylor & Francis.

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