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1.
Saudi J Biol Sci ; 25(8): 1546-1551, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30581316

RESUMO

Japanese encephalitis (JE), a viral disease has seen a drastic and fatal enlargement in the northern states of India in the current decade. The better and exact cure for the disease is still in waiting. For the cause an in silico strategy in the development of the peptide vaccine has been taken here for the study. A computational approach to find out the Major Histocompatibility Complex (MHC) binding peptide has been implemented. The prediction analysis identified MHC class I (using propred I) and MHC class II (using propred) binding peptides at an expectable percent predicted IC (50) threshold values. These predicted Human leukocyte antigen [HLA] allele binding peptides were further analyzed for potential conserved region using an Immune Epitope Database and Analysis Resource (IEDB). This analysis shows that HLA-DRB1*0101, HLA-DRB3*0101, HLA-DRB1*0401, HLA-DRB1*0102 and HLA-DRB1*07:01% of class II (in genotype 2) and HLA-A*0101, HLA-A*02, HLA-A*0301, HLA-A*2402, HLA-B*0702 and HLA-B*4402% of HLA I (in genotype 3) bound peptides are conserved. The predicted peptides MHC class I are ILDSNGDIIGLY, FVMDEAHFTDPA, KTRKILPQIIK, RLMSPNRVPNYNLF, APTRVVAAEMAEAL, YENVFHTLW and MHC class II molecule are TTGVYRIMARGILGT, NYNLFVMDEAHFTDP, AAAIFMTATPPGTTD, GDTTTGVYRIMARGI and FGEVGAVSL found to be top ranking with potential super antigenic property by binding to all HLA. Out of these the predicted peptide FVMDEAHFTDPA for allele HLA-A*02:01 in MHC class I and NYNLFVMDEAHFTDP for allele HLA-DRB3*01:01 in MHC class II was observed to be most potent and can be further proposed as a significant vaccine in the process. The reported results revealed that the immune-informatics techniques implemented in the development of small size peptide is useful in the development of vaccines against the Japanese encephalitis virus (JEV).

2.
Front Biosci (Landmark Ed) ; 23: 875-888, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28930578

RESUMO

We have investigated the anti-oxidative and glucose-lowering effects of 70% methanolic extract of H. heteroclita fruit pulp (MHE). Anti-oxidative property of MHE was assessed by free radical scavenging assays and compound level screening by LC-MS profiling. In silico analysis and in vivo preclinical validation were also performed using molecular docking and alloxan-induced diabetic model, respectively. MHE showed high anti-oxidant activity in DPPH radical scavenging assay with an IC50 of 0.37 µg/mL. The LC-MS profile of MHE substantiated the presence of p-hydroxy acids including benzoic, salicylic, p-coumaric, o-coumaric, caffeic, protocatechuic, gentisic, 2,4-dihydroxybenzoic, gallic, vanillic, syringic, and ferulic acids. Among these, caffeic acid was the most likely compound to interact with 1R0E at Val70, Ala83, Lys85, Gly97, Asp133, Val135, Leu188, Cys199, and Asp200, and with 1Q4L at Ile62, Ala83, Asp133, Tyr134, Val135, Arg141, and Val170. Treatment of rats with MHE showed significant reduction in serum glucose levels as compared to control rats. Taken together, the results show that MHE has compounds with anti-diabetic effect, which could be partially due to the anti-oxidant effects of the active components in MHE.


Assuntos
Cucurbitaceae/química , Frutas/química , Hipoglicemiantes/farmacologia , Extratos Vegetais/farmacologia , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/metabolismo , Masculino , Metanol/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/metabolismo , Ratos Wistar
3.
Interdiscip Sci ; 9(3): 378-391, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27052996

RESUMO

Transcription factors are trans-acting proteins that interact with specific nucleotide sequences known as transcription factor binding site (TFBS), and these interactions are implicated in regulation of the gene expression. Regulation of transcriptional activation of a gene often involves multiple interactions of transcription factors with various sequence elements. Identification of these sequence elements is the first step in understanding the underlying molecular mechanism(s) that regulate the gene expression. For in silico identification of these sequence elements, we have developed an online computational tool named transcription factor information system (TFIS) for detecting TFBS for the first time using a collection of JAVA programs and is mainly based on TFBS detection using position weight matrix (PWM). The database used for obtaining position frequency matrices (PFM) is JASPAR and HOCOMOCO, which is an open-access database of transcription factor binding profiles. Pseudo-counts are used while converting PFM to PWM, and TFBS detection is carried out on the basis of percent score taken as threshold value. TFIS is equipped with advanced features such as direct sequence retrieving from NCBI database using gene identification number and accession number, detecting binding site for common TF in a batch of gene sequences, and TFBS detection after generating PWM from known raw binding sequences in addition to general detection methods. TFIS can detect the presence of potential TFBSs in both the directions at the same time. This feature increases its efficiency. And the results for this dual detection are presented in different colors specific to the orientation of the binding site. Results obtained by the TFIS are more detailed and specific to the detected TFs as integration of more informative links from various related web servers are added in the result pages like Gene Ontology, PAZAR database and Transcription Factor Encyclopedia in addition to NCBI and UniProt. Common TFs like SP1, AP1 and NF-KB of the Amyloid beta precursor gene is easily detected using TFIS along with multiple binding sites. In another scenario of embryonic developmental process, TFs of the FOX family (FOXL1 and FOXC1) were also identified. TFIS is platform-independent which is publicly available along with its support and documentation at http://tfistool.appspot.com and http://www.bioinfoplus.com/tfis/ . TFIS is licensed under the GNU General Public License, version 3 (GPL-3.0).


Assuntos
Biologia Computacional/métodos , Fatores de Transcrição/metabolismo , Algoritmos , Sequência de Bases , Sítios de Ligação , Bases de Dados Genéticas , Matrizes de Pontuação de Posição Específica , Reprodutibilidade dos Testes
4.
Comput Biol Chem ; 65: 80-90, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27776248

RESUMO

The lack of complete treatments and appearance of multiple drug-resistance strains of Burkholderia cepacia complex (Bcc) are causing an increased risk of lung infections in cystic fibrosis patients. Bcc infection is a big risk to human health and demands an urgent need to identify new therapeutics against these bacteria. Network biology has emerged as one of the prospective hope in identifying novel drug targets and hits. We have applied protein-protein interaction methodology to identify new drug-target candidates (orthologs) in Burkhloderia cepacia GG4, which is an important strain for studying the quorum-sensing phenomena. An evolutionary based ortholog mapping approach has been applied for generating the large scale protein-protein interactions in B. Cepacia. As a case study, one of the identified drug targets; GEM_3202, a NH (3)-dependent NAD synthetase protein has been studied and the potential ligand molecules were screened using the ZINC database. The three dimensional structure (NH (3)-dependent NAD synthetase protein) has been predicted from MODELLERv9.11 tool using multiple PDB templates such as 3DPI, 2PZ8 and 1NSY with sequence identity of 76%, 50% and 50% respectively. The structure has been validated with Ramachandaran plot having 100% residues of NadE in allowed region and overall quality factor of 81.75 using ERRAT tool. High throughput screening and Vina resulted in two potential hits against NadE such as ZINC83103551 and ZINC38008121. These molecules showed lowest binding energy of -5.7kcalmol-1 and high stability in the binding pockets during molecular dynamics simulation analysis. The similar approach for target identification could be applied for clinical strains of other pathogenic microbes.


Assuntos
Antibacterianos/farmacologia , Burkholderia cepacia/efeitos dos fármacos , Simulação de Dinâmica Molecular , Ligação Proteica
5.
Biotechnol Appl Biochem ; 63(4): 497-513, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25913286

RESUMO

We examined the interaction of polycyclic hydrocarbons (PAHs) like benzo-α-pyrene (BaP), chrysene, and their metabolites 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene,9,10-oxide (BPDE) and chrysene 1,2-diol-3,4-epoxide-2 (CDE), with the enzymes involved in DNA repair. We investigated interaction of 120 enzymes with PAHs and screened out 40 probable targets among DNA repair enzymes, on the basis of higher binding energy than positive control. Out of which, 20 enzymes lose their function in the presence of BaP, chrysene, and their metabolites, which may fetter DNA repair pathways resulting in damage accumulation and finally leading to cancer formation. We propose the use of nanoparticles as a guardian against the PAH's induced toxicity. PAHs enter the cell via aryl hydrocarbon receptor (AHR). TiO2 NP showed a much higher docking score with AHR (12,074) as compared with BaP and chrysene with AHR (4,600 and 4,186, respectively), indicating a preferential binding of TiO2 NP with the AHR. Further, docking of BaP and chrysene with the TiO2 NP bound AHR complex revealed their strong adsorption on TiO2 NP itself, and not on their original binding site (at AHR). TiO2 NPs thereby prevent the entry of PAHs into the cell via AHR and hence protect cells against the deleterious effects induced by PAHs.


Assuntos
Benzopirenos/toxicidade , Crisenos/toxicidade , Biologia Computacional , Reparo do DNA/efeitos dos fármacos , Nanopartículas , Titânio/química , Titânio/farmacologia , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/metabolismo , Humanos , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Conformação Proteica , Titânio/metabolismo
6.
Interdiscip Sci ; 8(2): 192-201, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26260067

RESUMO

Determination of the native geometry of the enzymes and ligand complexes is a key step in the process of structure-based drug designing. Enzymes and ligands show flexibility in structural behavior as they come in contact with each other. When ligand binds with active site of the enzyme, in the presence of cofactor some structural changes are expected to occur in the active site. Motivation behind this study is to determine the nature of conformational changes as well as regions where such changes are more pronounced. To measure the structural changes due to cofactor and ligand complex, enzyme in apo, holo and ligand-bound forms is selected. Enzyme data set was retrieved from protein data bank. Fifteen triplet groups were selected for the analysis of structural changes based on selection criteria. Structural features for selected enzymes were compared at the global as well as local region. Accessible surface area for the enzymes in entire triplet set was calculated, which describes the change in accessible surface area upon binding of cofactor and ligand with the enzyme. It was observed that some structural changes take place during binding of ligand in the presence of cofactor. This study will helps in understanding the level of flexibility in protein-ligand interaction for computer-aided drug designing.


Assuntos
Enzimas/química , Cristalografia por Raios X , Bases de Dados de Proteínas , Ligantes , Ligação Proteica , Conformação Proteica
7.
Interdiscip Sci ; 7(2): 129-35, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26239541

RESUMO

Among CYPs, CYP2A sub-family is well known for its function to metabolise xenobiotics. CYP2A includes three members: CYP2A6, CYP2A7 and CYP2A13. Of these three proteins, structure and function of CYP2A6 and CYP2A13 are widely studied, whereas very little study has been carried out on CYP2A7. In the initial in vitro studies on CYP2A7, full protein in its active form could not be expressed. The exact structure and function of CYP2A7 is still not revealed. However, up-regulation of CYP2A7 has been reported in malignant oesophageal cells and colon cancer cells. In the present study, we generated the structure of CYP2A7 protein. The modelled proteins were validated and subjected to molecular docking analyses. The energy and RMSD calculations demonstrated that the protein is highly conserved in nature, i.e., the protein is not much flexible. Here the ligand molecules of NCI Diversity Set II from the ZINC database against the active site of the CYP2A7 protein were screened. Five compounds that possess good inhibitory activity against CYP2A7 active site were identified. The top ranking molecule (ZINC01572309) has a minimum energy score of -12.0 kcal/Mol. This compound is thus a good starting point for further development of strong inhibitors. Our in silico approach could help in better structural and functional analysis of CYP2A7. Apart from structural description of CYP2A7, elaboration of binding sites for inhibitors provides us with an opportunity to utilise binding pockets in targeted inactivation of this protein for further research.


Assuntos
Antineoplásicos/farmacologia , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Projeto Auxiliado por Computador , Inibidores das Enzimas do Citocromo P-450/farmacologia , Família 2 do Citocromo P450/antagonistas & inibidores , Desenho de Drogas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Antineoplásicos/química , Antineoplásicos/metabolismo , Hidrocarboneto de Aril Hidroxilases/química , Hidrocarboneto de Aril Hidroxilases/metabolismo , Sítios de Ligação , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/metabolismo , Família 2 do Citocromo P450/química , Família 2 do Citocromo P450/metabolismo , Humanos , Estrutura Molecular , Ligação Proteica , Reprodutibilidade dos Testes , Relação Estrutura-Atividade
8.
Artigo em Inglês | MEDLINE | ID: mdl-25877716

RESUMO

The degradation of intracellular proteins is targeted by ubiquitin via non-lysosomal proteolytic pathway in the cell system. These ubiquitin molecules have been found to be conserved from yeast to humans. Ubiquitin proteasome machinery utilises ATP and other mechanisms for degrading proteins of cytosol as well as nucleus. This process of ubiquitination is regulated by activating the E3 enzyme ligase, involved in phosphorylation. In humans, proteins which regulate the cell cycle are controlled by ubiquitin; therefore the ubiquitin-proteasome pathway can be targeted for novel anti-cancer strategies. Dysregulation of the components of the ubiquitin system has been linked to many diseases like cancer and inflammation. The primary triggering mechanism (apoptosis) of these diseases can also be induced when TNF-related apoptosis-inducing ligand (TRAIL) binds to its specific receptor DR4 and DR5. In this review, the emerging prospects and importance of ubiquitin proteasome pathway as an evolving anticancer strategy have been discussed. Current challenges in the field of drug discovery have also been discussed on the basis of recent patents on cancer diagnosis and therapeutics.


Assuntos
Neoplasias/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Desenho de Drogas , Humanos , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/patologia , Patentes como Assunto , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
9.
Interdiscip Sci ; 2015 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-25863964

RESUMO

Determination of the native geometry of the enzymes and ligand complexe is a key step in the process of structure based drug designing. Enzymes and ligands show flexibility in structural behavior as they come in contact with each other. When ligand binds with active site of the enzyme, in presence of cofactor some structural changes are expected to occur in the active site. Motivation behind this study is to determine the nature of conformational changes as well as regions where such changes are more pronounced. To measure the structural changes due to cofactor and ligand complex, enzyme in Apo, holo and ligand bound form is selected. Enzyme data set was retrieved from protein data bank (PDB). 15 triplet groups were selected for the analysis of structural changes based on selection criteria. Structural features for selected enzymes were compared at the global as well as local region. Accessible surface area for the enzymes in entire triplet set was calculated, which describes the change in accessible surface area upon binding of cofactor and ligand with the enzyme. It was observed that some structural changes take place during binding of ligand in presence of cofactor. This study will helps in understanding the level of flexibility in protein-ligand interaction for computer aided drug designing.

10.
Biotechnol Appl Biochem ; 62(5): 669-80, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25779642

RESUMO

TEM and SHV are class-A-type ß-lactamases commonly found in Escherichia coli and Klebsiella pneumoniae. Previous studies reported S130G and K234R mutations in SHVs to be 41- and 10-fold more resistant toward clavulanic acid than SHV-1, respectively, whereas TEM S130G and R244S also showed the same level of resistance. These selected mutants confer higher level of resistance against clavulanic acid. They also show little susceptibility against other commercially available ß-lactamase inhibitors. In this study, we have used docking-based virtual screening approach in order to screen potential inhibitors against some of the major resistant mutants of SHV and TEM types ß-lactamase. Two different inhibitor-resistant mutants from SHV and TEM were selected. Moreover, we have retained the active site water molecules within each enzyme. Active site water molecules were placed within modeled structure of the mutant whose structure was unavailable with protein databank. The novelty of this work lies in the use of multilayer virtual screening approach for the prediction of best and accurate results. We are reporting five inhibitors on the basis of their efficacy against all the selected resistant mutants. These inhibitors were selected on the basis of their binding efficacies and pharmacophore features.


Assuntos
Farmacorresistência Bacteriana/efeitos dos fármacos , Modelos Moleculares , Mutação , Homologia de Sequência de Aminoácidos , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/química , beta-Lactamases/metabolismo , Sequência de Aminoácidos , Domínio Catalítico , Avaliação Pré-Clínica de Medicamentos , Farmacorresistência Bacteriana/genética , Simulação de Acoplamento Molecular , Dados de Sequência Molecular , Interface Usuário-Computador , Água/química , Inibidores de beta-Lactamases/metabolismo , beta-Lactamases/genética
11.
Interdiscip Sci ; 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25519152

RESUMO

Among CYPs, CYP2A sub-family is well known for its function to metabolize xenobiotics. CYP2A includes three members: CYP2A6, CYP2A7 and CYP2A13. Of these three proteins, structure and function of CYP2A6 and CYP2A13 are widely studied whereas very little study has been carried out on CYP2A7. In the initial in vitro studies on CYP2A7, full protein in its active form could not be expressed. The exact structure and function of CYP2A7 is still not revealed. However, up-regulation of CYP2A7 has been reported in malignant oesophageal cells and colon cancer cells. In the present study, we generated the structure of CYP2A7 protein. The modelled proteins were validated and subjected to molecular docking analyses. The energy and RMSD calculations demonstrated that the protein is highly conserved in nature i.e. the protein is not much flexible. Here the ligand molecules of NCI Diversity Set II from the ZINC database against the active site of the CYP2A7 protein were screened. Five compounds that possess good inhibitory activity against CYP2A7 active site were identified. The top ranking molecule (ZINC01572309) has a minimum energy score of -12.0 Kcal/Mol. This compound is thus a good starting point for further development of strong inhibitors. Our in silico approach could help in better structural and functional analysis of CYP2A7. Apart from structural description of CYP2A7, elaboration of binding sites for inhibitors provides us with an opportunity to utilize binding pockets in targeted inactivation of this protein for further research.

12.
Artigo em Inglês | MEDLINE | ID: mdl-25409874

RESUMO

Coxiella burnetii is an infectious and etiological agent responsible for causing Q fever. There are mainly two forms of the Q fever that are chronic and acute. Though the acute type is usually linked with symptoms like pneumonia and hepatitis, the chronic form is shown to have mortality rate of 5%. Percentage of mortality rate might increases from 5% to 25% if left untreated. The present treatments of disease include the recommended dose of drugs and vaccine. Presently, extensive attempt is in progress to find novel therapies to combat the disease. This review is projected to provide a brief introduction of C. burnetii and Q fever while emphasizing therapeutics, prophylactic measures and diagnostic applications based on recent patents prospects.


Assuntos
Antibacterianos/uso terapêutico , Febre Q/tratamento farmacológico , Vacinas Bacterianas/uso terapêutico , Doxiciclina/uso terapêutico , Farmacorresistência Bacteriana , Fluoroquinolonas/uso terapêutico , Humanos , Patentes como Assunto , Febre Q/diagnóstico , Febre Q/prevenção & controle
13.
Bioinformation ; 10(8): 496-501, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25258484

RESUMO

Japanese encephalitis (JE) is an acute viral infection of the central nervous system where the JE virus infects the lumen of the endoplasmic reticulum (ER) and rapidly accumulates substantial amount of seven different nonstructural proteins (NS). These NS proteins tend to bind on a glycoprotein receptor, ribophorin (RPN) resulting in the malfunctioning of ER in host cells, subsequently triggering an unfolded protein response. Therefore, it is of interest to predict the best possible antigenic determinants in the NS protein capable of eliciting immune response as a strategy to combat JE. Hence, it is our interest to explore the most potent NS protein among all showing the best possible molecular interaction with the RPN receptor present on ER. However, the structures of these NS protein and RPN are currently unknown. Thus, we modeled their structures using the established homology modeling techniques in the MODELLER 9v10 software. The molecular docking of NS proteins with RPN was subsequently completed using the Discovery Studio 2.5 software suite. The docked conformations of RPN with NS were further analyzed and its graphical interpretations were presented for identifying the most potential NS protein for efficient epitope activity. Further, the B cell epitopes were mapped using BCPred and the predicted epitope regions are documented. The data presented in this report provides useful insights towards the design and development of potential epitopes to generate a vaccine candidate against JEV.

14.
Artigo em Inglês | MEDLINE | ID: mdl-25145329

RESUMO

Anthrax is one of the deadly infectious disease as documented in the CDC website. In spite of the availability of appropriate antimicrobial agents, the mortality related with the anthrax remains high. The pathogenicity of B. anthracis is mainly accredited to the two foremost components: toxins and capsule. Virulence component of B. anthracis includes protective antigen (PA) which plays a vital role in pathogenesis, virulence protein edema factor (EF) and lethal factor (LF). This search for novel therapeutic strategies that attack the proteins involved in the pathogenesis of anthrax and may potentially supplement antimicrobials being investigated. Currently, extensive attempts are in progress to develop novel helpful therapies to all of the virulence components: lethal factor, protective antigen, edema factor and the capsule of B. anthracis. This review discusses the potential anthrax therapeutic, prophylactic measures and diagnostic applications based on recent patents' prospects.


Assuntos
Antraz/diagnóstico , Antraz/tratamento farmacológico , Animais , Antígenos de Bactérias/metabolismo , Bacillus anthracis/efeitos dos fármacos , Toxinas Bacterianas/metabolismo , Humanos , Patentes como Assunto , Fatores de Virulência/metabolismo
15.
J Mol Model ; 20(7): 2340, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24990796

RESUMO

The degradation of hydrocarbons plays an important role in the eco-balancing of petroleum products, pesticides and other toxic products in the environment. The degradation of hydrocarbons by microbes such as Geobacillus thermodenitrificans, Burkhulderia, Gordonia sp. and Acinetobacter sp. has been studied intensively in the literature. The present study focused on the in silico protein engineering of alkane monooxygenase (ladA)-a protein involved in the alkane degradation pathway. We demonstrated the improvement in substrate binding energy with engineered ladA in Burkholderia thailandensis MSMB121. We identified an ortholog of ladA monooxygenase found in B. thailandensis MSMB121, and showed it to be an enzyme involved in an alkane degradation pathway studied extensively in Geobacillus thermodenitrificans. Homology modeling of the three-dimensional structure of ladA was performed with a crystal structure (protein databank ID: 3B9N) as a template in MODELLER 9v11, and further validated using PROCHECK, VERIFY-3D and WHATIF tools. Specific amino acids were substituted in the region corresponding to amino acids 305-370 of ladA protein, resulting in an enhancement of binding energy in different alkane chain molecules as compared to wild protein structures in the docking experiments. The substrate binding energy with the protein was calculated using Vina (Implemented in VEGAZZ). Molecular dynamics simulations were performed to study the dynamics of different alkane chain molecules inside the binding pockets of wild and mutated ladA. Here, we hypothesize an improvement in binding energies and accessibility of substrates towards engineered ladA enzyme, which could be further facilitated for wet laboratory-based experiments for validation of the alkane degradation pathway in this organism.


Assuntos
Alcanos/metabolismo , Proteínas de Bactérias/metabolismo , Burkholderia/enzimologia , Oxigenases de Função Mista/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Engenharia de Proteínas , Sequência de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Sítios de Ligação , Burkholderia/genética , Cristalização , Bases de Dados de Proteínas , Oxigenases de Função Mista/química , Oxigenases de Função Mista/genética , Dados de Sequência Molecular , Mutação , Ligação Proteica , Conformação Proteica , Homologia de Sequência , Relação Estrutura-Atividade , Especificidade por Substrato
16.
Artigo em Inglês | MEDLINE | ID: mdl-25019389

RESUMO

Affecting more than one third of the world population, tuberculosis remains one of the world's most dreadful diseases, with no easy cures. Mycobacterial infestation and the evasion of host immune response are significantly responsible for the emergence of pulmonary tuberculosis. Mycobacterium tuberculosis, a weak gram positive, facultative aerobe colonizes in respiratory regions rich in oxygen reserves. Up regulation of CR and MR expression and function due to signaling by LAM results in electing immuno regulatory cytokines IL-4, IL-8 and Th2. Binding of NF-κB complex with mRNA prevention, due to mutation of leucine zipper domain of IK, inhibits the activation of cytokines and receptor molecules. Mechanism of energy generation by conversion of ADP to ATP, initiated by utilizing intermediary and/or end products of carbohydrate, amino acid or fatty acid catabolism is essential in approximating potential drug targets for elimination of the bacterium. A few improved diagnostic techniques have been evaluated over the last few years like Interferon Gamma Relese Assays, Nucleic Acid Amplification tests etc. of which most have certainly proven to facilitate specific detection of TB. Drugs like Rifampicin, Isoniazid etc. have also shown great curing effects on TB patients. Further research is required for better understanding of mechanism of pathogenesis and multiple drug resistance issues for developing the effective therapeutics and diagnostics against TB. The paper focuses on the effective diagnostics and therapeutics applications for tuberculosis prevention and cure based on recent patents and their analysis.


Assuntos
Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Patentes como Assunto
17.
Artigo em Inglês | MEDLINE | ID: mdl-24605908

RESUMO

The genetic alterations and aberrant miRNA expression profiles have been identified as important events behind the emergence of cancer. This knowledge triggers the use of miRNA therapeutics as an anticancer strategy. Basically, MicroRNAs (miRNAs) are approximately 22-nucleotide long, endogenous non-protein-coding RNA molecules which function as important regulatory molecules that regulate gene and protein expression through the RNA interference (RNAi) machinery. Transcription of these molecules by RNA polymerases II and III, resulting in the generation of precursor microRNAs that undergo a series of cleavage events, consequently, generate the mature microRNA. The biogenesis pathway is mediated by the two important cleavage events such as nuclear and cytoplasmic. The regulatory functions of microRNAs are accomplished through the RNA-induced silencing complex (RISC), leading to translational repression and hence, regulate the gene expression. The current progress in the development of strategies for miRNA-based anticancer therapies is due to its involvement in cellular, developmental and biological processes including regulation in cancer cell and modulation by various cancer chemoprophylaxis agents. Although miRNA therapeutics have been found to suppress gene expression effectively as compared to anti-sense oligonucleotide strategies, but it is bound with some limitations viz. identification of tissue specific miRNA, biological instability, off-target effects and delivery in the cell system. Up to certain extent, these hurdles have been resolved by chemical modifications using cholesterol conjugation, morpholinos, cationic lipids and cationic nanoparticles. Still more research is needed to understand the mechanism of action for better miRNA therapeutics. The paper discusses the potential miRNA therapeutics and diagnostic applications for cancer prevention, based on recent patents and their analysis.


Assuntos
Antineoplásicos/farmacologia , MicroRNAs/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/uso terapêutico , Humanos , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Neoplasias/metabolismo , Oncogenes/genética , Patentes como Assunto , Interferência de RNA
18.
Mol Biol Rep ; 41(6): 3951-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24652202

RESUMO

Rab3A is expressed predominantly in brain and synaptic vesicles. Rab3A is involved specifically in tethering and docking of synaptic vesicles prior to fusion which is a critical step in regulated release of neurotransmitters. The precise function of Rab3A is still not known. However, up-regulation of Rab3A has been reported in malignant neuroendocrine and breast cancer cells. In the present study, the structure of Rab3A protein was generated using MODELLER 9v8 software. The modeled protein structure was validated and subjected to molecular docking analyses. Docking with GTP was carried out on the binding site of Rab3A using GOLD software. The Rab3A-GTP complex has best GOLD fitness value of 77.73. Ligplot shows hydrogen bondings (S16, S17, V18, G19, K20, T21, S22, S31, T33, A35, S38, T39 and G65) and hydrophobic interacting residues (F25, F32, P34, F36, V37, D62 and A64) with the GTP ligands in the binding site of Rab3A protein. Here, the ligand molecules of NCI diversity set II from the ZINC database against the active site of the Rab3A protein were screened. For this purpose, the incremental construction algorithm of GLIDE and the genetic algorithm of GOLD were used. Docking results were analyzed for top ranking compounds using a consensus scoring function of X-Score to calculate the binding affinity and Ligplot was used to measure protein-ligand interactions. Five compounds which possess good inhibitory activity and may act as potential high affinity inhibitors against Rab3A active site were identified. The top ranking molecule (ZINC13152284) has a Glide score of -6.65 kcal/mol, X-Score of -3.02 kcal/mol and GOLD score of 64.54 with 03 hydrogen bonds and 09 hydrophobic contacts. This compound is thus a good starting point for further development of strong inhibitors.


Assuntos
Carcinogênese/química , Simulação de Acoplamento Molecular , Proteína rab3A de Ligação ao GTP/química , Sítios de Ligação , Domínio Catalítico , Humanos , Ligantes , Conformação Molecular , Bibliotecas de Moléculas Pequenas/química , Proteína rab3A de Ligação ao GTP/antagonistas & inibidores , Proteína rab3A de Ligação ao GTP/genética
19.
Bioinformation ; 9(18): 923-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24307771

RESUMO

Solanum lycopersicum and Solanum tuberosum are agriculturally important crop species as they are rich sources of starch, protein, antioxidants, lycopene, beta-carotene, vitamin C, and fiber. The genomes of S. lycopersicum and S. tuberosum are currently available. However the linear strings of nucleotides that together comprise a genome sequence are of limited significance by themselves. Computational and bioinformatics approaches can be used to exploit the genomes for fundamental research for improving their varieties. The comparative genome analysis, Pfam analysis of predicted reviewed paralogous proteins was performed. It was found that S. lycopersicum proteins belong to more families, domains and clans in comparison with S. tuberosum. It was also found that mostly intergenic regions are conserved in two genomes followed by exons, intron and UTR. This can be exploited to predict regions between genomes that are similar to each other and to study the evolutionary relationship between two genomes, leading towards the development of disease resistance, stress tolerance and improved varieties of tomato.

20.
Bioinformation ; 9(1): 54-60, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23390345

RESUMO

4-hydroxypanduratin A is a secondary metabolite of Boesenbergia pandurata Schult. (Fingerroot) plant with various pharmacological activities such as neuroprotective, potent antioxidant, antibacterial and antifungal. Flaviviral NS2B/NS3 protease activity is essential for polyprotein processing and viral replication for Japanese Encephalitis Virus (JEV), a major cause of Acute Encephaltis in Asia. Inhibition of formation of this complex by arresting the binding of NS2B with NS3 would reduce the enzyme's activity to meager proportions and hence would prevent further viral proliferation. The automated 3D structure of NS2B protein of the JEV GP78 was predicted based on the sequence-to-structure-to-function paradigm using I-TASSER and the function of NS2B protein was inferred by matching to other known proteins. The stereochemical quality of predicted structure was checked by PROCHECK. The antiviral activity of 4-hydroxypanduratin A against NS2B protein as a potential drug has been elucidated in this paper. Docking simulation analysis showed 4-hydroxypanduratin A as potential inhibitor of NS2B protein/cofactor which is necessary for NS3 protease activity. 220 derivatives of 4-hydroxypanduratin A were virtually screened with rigid criteria of Lipinski's rule of 5 using Autodock4.2. 4-hydroxypanduratin A was found interacting with target hydrophilic domain in NS2B protein by two Hbonds (Gly80 and Asp81) with active residues, several hydrophobic interactions, Log P value of 5.6, inhibition constant (Ki) of 51.07nM and lowest binding energy of -9.95Kcal/Mol. Hence, 4-hydroxypanduratin A targeted to Site 2 will have sufficient profound effect to inhibit protease activity to abrogate viral replication. It could be a promising potential drug candidate for JEV infections using NS2B Site 2 as a Drug target.

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