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http://www.webmedcentral.com/images/Header_Logo.giftext/html2010-08-23T20:40:25+01:00http://www.webmedcentral.com/Mr. Kranthi Raj KAn Efficient Pharmacophore Generation Strategy To Identify New Leukotriene A4 Hydrolase (lta4h)
http://www.webmedcentral.com/article_view/501
Leukotriene A4 Hydrolase as a potent inhibitor in inflammation. Leukotriene A4 hydrolase, also known as LTA4H is a human gene. The protein encoded by this gene, a bifunctional zinc enzyme converts leukotriene A4 to leukotriene B4 (LTB4). Arachidonic acid is a polyunsaturated fatty acid that is present in the phospholipids of membranes of the body's cells, and is abundant in the brain. It is involved in cellular signaling as a lipid second messenger. LTA4H may play an important role in carcinogenesis, especially chronic inflammation-associated carcinogenesis by two ways.
a) The inflammation-augmenting effect of inflammatory cells through positive
b) The autocrine growth-stimulatory effect of LTB4 produced by epithelial cells, and the paracrine growthstimulatory effect of LTB4 produced by inflammatory cells, on precancerous and cancer cells.
Many drugs like Bestatin (N-[(2S,3R)-3-amino-2-hydroxy-4-phenyl-butanoyl]-L-leucine), Thioamine (3-(4-benzyloxyphenyl)-2-(R)-amino-1-propane thiol) Hydroxamicacid((N-hydroxy-N-[(2S)-2-amino-3-(benzyloxyphenyl)propyl]-5-carboxypentanamide) are available in the market which inhibits hydrolase activity. The variability in potency found in LTA4H inhibitors (50% inhibitory concentrations (IC50s) ranging from submicromolar to high-micr-omolar values for structurally related molecules) suggests that accessory binding pockets in the enzyme active site must be present and play a pivotal, still unclarified, role in determining the affinity. It is therefore conceivable that the identification of such areas can be exploited for the design of novel, more potent LTA4H inhibitors.
In view of the potential therapeutic importance of LTA4H inhibitors, we engaged ourselves in a program devoted to the design feature based three-dimensional pharmacophore model for LTA4H inhibitors. In this frame, we report here a molecular modeling study aimed at mapping the topography of the active site of LTA4H and at identifying the structural requirement for LTA4H inhibition. Many LTA4H inhibitors for which homogeneous biological values are available were collected from the literature along with their inhibitory IC50 values. The Generated model can be further utilized for developing new potentially active candidates targeting LTA4H, which can be useful as anti inflammation agents.text/html2011-02-25T22:19:15+01:00http://www.webmedcentral.com/Dr. Andrew D JohnsonRNA Structures Affected By Single Nucleotide Polymorphisms In Transcribed Regions Of The Human Genome
http://www.webmedcentral.com/article_view/1600
Single-stranded RNAs fold into base-paired structures sometimes critical for RNA function.We report the first genome-wide computational analysis of mRNA structures, obtaining predicted minimum free energy structures (MFE) and ensembles of top-scoring structures.Evaluation of mRNA structures from >12,450 genes indicates that thermodynamically favorable structures preferentially form within specific regions of some human mRNAs.High energy and conserved structures occur more often than expected within untranslated regions, and in coding exons in proximity to translation start sites and in-frame methionine codons.Several genetic variants within these structures are already known to contribute to human diseases.To investigate the impact of polymorphisms on RNA structures more broadly, we examined the effects of 153,397 single nucleotide polymorphisms (SNPs) in exons of the human genome on RNA structures, including splice variants.The majority of human exonic SNPs are predicted to alter RNA structure to some degree (~60% affect MFEs and >90% the ensembles). Predicted secondary structural effects are localized to SNP regions within ~50 base-pairs. We find structural (epistatic) interactions between SNP bases within some haplotypes suggesting possible covariation preserving specific structures.Further analyses of SNPs within known functional RNA structures (IREs, SECIS, miRNAs, snoRNAs) identify a number of putative functional SNPs, many within genes already associated with human phenotypes, and suggest that conformational RNA polymorphisms substantially contribute to human phenotypic variability. Comparison of SNP-RNA structures against published genome-wide association (GWAS) results indicates that some strong genetic signals from GWAS (e.g., LPL, AGER) may exhibit their functional effects through modified RNA structures that could impact RNA stability, alternative RNA or protein processing, or translational efficiency. Our genome-wide evaluation of RNA structures, combined with the structural effects predicted for human SNPs, yields information useful for structure-function studies on RNAs and genetic variants.text/html2010-09-26T07:24:41+01:00http://www.webmedcentral.com/Dr. Eric SakkEvaluation of neural network performance in the protein secondary structure prediction problem
http://www.webmedcentral.com/article_view/632
In the context of the protein secondary structure prediction problem, we examine the performance of various neural network architectures commonly applied in the literature. Specifically,by applying the neural network paradigm, mappings between training vectors and their desired targets are constructed. The class membership of test data and associated measures of significance are then numerically demonstrated to vary depending on the set of applied target vectors. By applying standard symbol encoding techniques, we analyze and discuss the ability of the neural network to accurately model fundamental attributes of protein secondary structure.text/html2010-10-16T13:07:49+01:00http://www.webmedcentral.com/Prof. Shaibu O BelloCross Platform In Silico Design And Evaluation Of Small Interfering Rnas That Target The Expression Of Plasmodium Falciparum Heat Shock Protein 90 (pfhsp90) Gene
http://www.webmedcentral.com/article_view/1005
It has been shown that it is both efficient and cost effective to run experiments in silico before actual laboratory work in real time. Plasmodium falciparum heat shock protein 90(pfHsp90) appears sufficiently different from the human type to serve as an appropriate drug target. This expectation will need to be evaluated by targeted silencing of the expression of this protein. It is considerably much cheaper and effective to conduct as much of the study in silico. This report presents the design and evaluation of small interfering RNAs that target the mRNA of pfHsp90.text/html2011-08-30T12:00:14+01:00http://www.webmedcentral.com/Ms. Jayadeepa RMIn Silico Techniques for the Identification of Novel Natural Compounds for Secreting Human Breast Milk
http://www.webmedcentral.com/article_view/2131
Low milk supply is an abounding problem endured by the pregnant women in every country. Many of them consume herbs and vegetables to stimulate the secretion of the breast milk. Some of the commercially available drugs that are used for the purpose are domperidone, metachlopromide (reglan) and many more. The main objective of the research work is to make out the chemical components enclosed within the natural galactogogues (milk stimulating products). A total of 157 compounds were collected. Most of them were found in herbs such as alfalfa, fenugreek and other sources like ginger, onion, oats etc. In view of the project the prolactin receptor signaling pathway was taken into account since prolactin hormone is the chief hormone leading to lactation. For the purpose, the prolactin receptor complexed with prolactin hormone (3NPZ) was spotted as the targeted protein. The collected molecules were screened on the basis of Lipinski's rule, and docking score. From the screened compounds the better interacting compounds were made out on the basis of their binding with the receptor through the Q-site finder. namely Sesamin, Quercetin, Kampferol, Trifoliol, Limonin were found to be the better interacting components that can be tabbed for the lead compound for stimulating the breast milk production.text/html2011-11-10T15:57:26+01:00http://www.webmedcentral.com/Mr. Rohit ChouguleDocking Studies of Tryptic Peptides from Colostrum β-Lactoglobulin to Matrix Metalloproteinase 9 (MMP-9)
http://www.webmedcentral.com/article_view/2447
Matrix metalloproteinases (MMPs), the class of enzymes involved in the degradation of extra cellular matrix and surrounding cells are known to be expressed during cancer cell invasion, arthritis and metastasis and MMP-9, in particular seems to be a key protease associated with tumor progression. Therefore development of inhibitors of MMP-9 is a challenging task which can have therapeutic benefit for patients suffering from various cancers.β-lactoglobulin (β-LG), a core member of lipocalin (Lcn)family is an abundant whey protein in milk of ruminants and has attracted considerable attention as a rich source of bioactive peptides involved in diverse biological functions. Many of the lipocalins are shown to possess protease inhibitory activity including Lcn-2 and β-LG being a major lipocalin, its tryptic peptides were verified for the inhibitory effect on MMP-9.Hence, to investigate the effect of β-LG peptides on the protease activity, we have used β-LG purified from buffalo colostrum.The tryptic peptides of β-LG were separated and analyzed by LC-MS/MS. Based on in silico analysis the sequence information for singly charged peptide ions, m/z-573 IIAEK (P1), m/z-673 GLDIQK (P2), m/z-916 IDALNENK(P3) and m/z-933 IIVTQTMK (P4) were deduced and the interaction of these peptides with MMP-9 was verified by validated target of Matrix metalloproteinase-9 (PDB: 1GKC) using MolDock. A good correlation was observed in binding affinity of hypocholesterolemic peptides (IIAEK & GLDIQK) along with other two peptides (IDALNENK & IIVTQTMK) of β-LG from the buffalo colostrum implicating its utilization in functional foods.Keywords: β-lactoglobulin, LC-MS/MS, Collision induced dissociation, In silico analysis, Matrix metalloproteinases, Molecular docking.text/html2011-12-30T16:23:25+01:00http://www.webmedcentral.com/Mr. S M Sabbir AlamHomology Modeling and Docking Studies Showed that Dihydrofolate Reductase from Pseudomonas Putida is a Possible Choice for Diagnosis of Serum Trimethoprim by Enzyme Inhibiton Assay
http://www.webmedcentral.com/article_view/2825
Trimethoprim is a chemotherapeutic drug mainly used in prophylaxis and treatment of bacterial infections. It belongs to dihydrofolate reducase inhibitors and has bacteriostatic properties. It may cause serious side effects if it is overdosed or used for long time. It may cause renal clearance mechanism impairment, thrombocytopenia, allergic reactions and a number of other clinical complications. An enzyme inhibition assay can be used to determine serum trimethoprim, which may provide advantage in terms of time and cost. This involves inhibition of dihydrofolate reductase by trimethoprim in serum. Dihydrofolate reductase (DHFR) is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid. In this study DHFR from lactobacillus casei (PDB id: 4DFR:A), Bacillus anthracis (PDB id:3JW3_A) and Moritella profunda (PDB id: 3IA4_A) are used as templates for building 3D models of DHFR from some other species. Programs used here are MODELLER, SWISS 3D MODEL and GENO3D. Based on overall stereochemical quality (PROCHECK, VARIFY3D, ANOLEA, PROSA) best models were selected, refined and characterized for binding site by CASTp program along with Catalytic Site Atlas (CSA) database. Best models were studied further for structure function relationship with ligand (trimethoprim) and its analogue (dihydrofolate reductase) by using docking approach (AutoDock and AutoDock VINA). The interaction energy between the trimethoprim and modeled enzyme indicated that homology models for DHFR of Pseudomonas putida can account for better regionspecificity of this enzyme towards trimethoprim. Findings from the current study could be utilized to de novo enzyme selection for diagnosis of serum trimethoprim.text/html2012-04-28T10:08:55+01:00http://www.webmedcentral.com/Mr. Krishnanand P KulkarniIn Silico Identification of Rice Gene Homologues in Brachypodium, Sorghum and Maize: Insight into Development of Gene Specific Markers
http://www.webmedcentral.com/article_view/3258
Rice, one of the important cereal species, is considered as a model for studying grass family. Whole rice genome is recently sequenced, fully annotated and hundreds of genes are characterized. Molecular resources in rice are ever increasing since the draft became publicly available and the information is being utilized to study other cereal genomes as well. This study presents a comprehensive identification of rice genes for important traits like biotic and abiotic stress tolerance and grain yield and design of gene-specific PCR-based markers. A total of 925 functionally characterized genes were identified through literature and searched for their homologue counterparts in three different cereal genomes. The identified homologs found to be syntenic in their relationship with rice and may have shared a common ancestor. Selected set of genes was mined for presence of microsatellite repeat motifs and primers were designed flanking those repeat motifs. These markers will find great usage in phenotyping for stress tolerance or any other trait of interest in related cereal crops and in selecting genotypes in breeding program aimed at transferring a particular gene in an elite genetic background. In addition, these markers can be used as probes in comparative genome analyses.text/html2016-01-18T09:19:26+01:00http://www.webmedcentral.com/Dr. Robert RicketsonThe Glycoprotein Mucin-Like Domain (MLD) in the Zaire ebolavirus (EBOV) may be responsible for the manifestations of Post-Ebola Virus Disease Syndrome (PEVDS)
http://www.webmedcentral.com/article_view/5042
The incidence of various ocular, CNS, and musculoskeletal complaints in the convalescent period following recovery from Ebola Virus Disease (PEVDS) has become an intense area of interest in the aftermath of the recent West Africa outbreak 2014-2015. A review of past outbreaks involving EBOV, SUDV, TAFV, and BDBV revealed similar, but poorly documented symptoms in the convalescent period. Additionally, viable virus has been identified in the recovery phase in sperm and ocular fluid up to 9 months after recovery with no evidence of viremia. A prior study by Yang in 2000 demonstrated the mucin-like domain was responsible for the vascular permeability and inflammation seen in EVD with Zaire ebolavirus infections but not in Reston ebolavirus infections.
To study the mucin-like domain further, a comparative multi-sequence amino acid analysis of the poorly conserved MLD was performed and all 16 B-cell epitopes previously identified comparing all virulent species of Ebolavirus against RESTV was used to identify regions that could explain the differential virulence and vascular access to regions of immune privileged regions. Within the E1 epitope (301-316) of the MLD, the charged motif R (X1) EELSF demonstrated significant homology (86%) within the virulent species but poorly conserved in RESTV (25%). In E5-E8, charged tandem grouping of charged residues in the motif Glu-336, Asp-337, and His-338 of EBOV were conserved as to charge in the virulent group but these charged residues were replaced by the uncharged Pro-336, Thr-337, and Arg-338 in the RESTV sequence. The C-terminus GLINT motif in epitope E16 of the MLD at the GP2 junction was moderately conserved between all species including RESTV and therefore not felt to contribute to the overall differential virulence.
Within the MHC class I predictions, there did not appear to be a statistically significant difference between the virulent species and RESTV. However, the MHC Class II predicted epitopes did identify a statistically significant difference between the virulent species and RESTV. Three epitopes of acceptable binding affinities in the virulent group were significantly different from RESTV (p>.05)
This study suggests that the residues located within the B-cell E1 epitope (301-316) and three MHC Class II epitopes may be responsible for vascular access to these immune privileged site and persistent symptoms observed in the convalescent PEVDS. Further studies are required into the potential role of VP40 in viral persistence and reemergence within these immune privileged areas; therefore potentially provide a therapeutic strategy in PEVDS and viral persistence associated with reemergence.text/html2016-11-01T11:20:11+01:00http://www.webmedcentral.com/Dr. Kamaraju RaghavendraA short note on comparative analysis of acetylcholinesterase genes in mosquito genome
http://www.webmedcentral.com/article_view/5209
Acetylcholineserase genes confer the organophosphate and carbamate resistance mechanism. A total of 46 acetylcholineserase genes in the 24 mosquito genomes were identified. In this study, all the analysed mosquito genomes have the two acetylcholinesterase genes (ace-1 and ace-2) except Aedes albopictus and Anopheles sinensis- sinensis strain. Phylogenetic tree showed the divergence of acetylcholinesterase genes among the mosquito genome. Phylogenetic tree confirmed that the ace-1 and ace-2 genes of each species were structurally different and they form the different clades. This provided data on acetylcholinesterase gene organization for 24 mosquito genome is possibly a first time and will be a starting point for the molecular characterization of the acetylcholinesterase genes which further helps to understand the organophosphate and carbamate resistance mechanism.