Current Issue : January - March Volume : 2013 Issue Number : 1 Articles : 7 Articles
The present investigation focuses on the discovery of novel PDE4 inhibitor for Glomerulonephritis Asthma, COPD a Bipolar depression autoimmune encephalomyelitis. In this context, we have identified novel lead zinc_8442272 using target search option in the zinc database. The docking analysis revealed that ligand zinc_8442272 interacts with PDE4 enzyme through hydrogen bonding, arene-arene, polar interactions and nonbonding interactions. The analysis conclude that para substituted methoxy group, benzene ring on both terminal, sulphonamide substituent are essential for PDE4 inhibition. Further substitution of any hydrogen bond acceptor on benzene ring over second terminal may be beneficial enhancing PDE4 inhibition....
Background: Protein-DNA docking is a very challenging problem in structural bioinformatics and has important\r\nimplications in a number of applications, such as structure-based prediction of transcription factor binding sites\r\nand rational drug design. Protein-DNA docking is very computational demanding due to the high cost of energy\r\ncalculation and the statistical nature of conformational sampling algorithms. More importantly, experiments show\r\nthat the docking quality depends on the coverage of the conformational sampling space. It is therefore desirable\r\nto accelerate the computation of the docking algorithm, not only to reduce computing time, but also to improve\r\ndocking quality.\r\nMethods: In an attempt to accelerate the sampling process and to improve the docking performance, we\r\ndeveloped a graphics processing unit (GPU)-based protein-DNA docking algorithm. The algorithm employs a\r\npotential-based energy function to describe the binding affinity of a protein-DNA pair, and integrates Monte-Carlo\r\nsimulation and a simulated annealing method to search through the conformational space. Algorithmic techniques\r\nwere developed to improve the computation efficiency and scalability on GPU-based high performance computing\r\nsystems.\r\nResults: The effectiveness of our approach is tested on a non-redundant set of 75 TF-DNA complexes and a newly\r\ndeveloped TF-DNA docking benchmark. We demonstrated that the GPU-based docking algorithm can significantly\r\naccelerate the simulation process and thereby improving the chance of finding near-native TF-DNA complex\r\nstructures. This study also suggests that further improvement in protein-DNA docking research would require\r\nefforts from two integral aspects: improvement in computation efficiency and energy function design.\r\nConclusions: We present a high performance computing approach for improving the prediction accuracy of\r\nprotein-DNA docking. The GPU-based docking algorithm accelerates the search of the conformational space and\r\nthus increases the chance of finding more near-native structures. To the best of our knowledge, this is the first ad\r\nhoc effort of applying GPU or GPU clusters to the protein-DNA docking problem....
Structural symmetry in homooligomeric proteins has intrigued many researchers over the past several decades. However,\r\nthe implication of protein symmetry is still not well understood. In this study, we performed molecular dynamics (MD)\r\nsimulations of two forms of trp RNA binding attenuation protein (TRAP), the wild-type 11-mer and an engineered 12-mer,\r\nhaving two different levels of circular symmetry. The results of the simulations showed that the inter-subunit fluctuations in\r\nthe 11-mer TRAP were significantly smaller than the fluctuations in the 12-mer TRAP while the internal fluctuations were\r\nlarger in the 11-mer than in the 12-mer. These differences in thermal fluctuations were interpreted by normal mode analysis\r\nand group theory. For the 12-mer TRAP, the wave nodes of the normal modes existed at the flexible interface between the\r\nsubunits, while the 11-mer TRAP had its nodes within the subunits. The principal components derived from the MD\r\nsimulations showed similar mode structures. These results demonstrated that the structural symmetry was an important\r\ndeterminant of protein dynamics in circularly symmetric homooligomeric proteins....
Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is considered a promising strategy for the treatment\r\nof Alzheimerâ��s disease (AD). This research project aims to provide a comprehensive knowledge of newly synthesized coumarin\r\nanalogues with anti-AD potential. In the present work a series of 3-thiadiazolyl- and thioxo-1,2,4-triazolylcoumarins derivatives\r\nwere designed, synthesized, and tested as potent inhibitors of cholinesterases. These compounds were assayed against AChE from\r\nelectrophorus electricus and rabbit; and BChE from horse serum and rabbit by Ellmanâ��s method using neostigmine methylsulphate\r\nand donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors of AChE and BChE with Ki values\r\nin the micromolar range. 4b was found to be the most active compound with Ki value 0.028 �± 0.002 �µM and higher selectivity for\r\nAChE/BChE. The ability of 4b to interact with AChE was further confirmed through computational studies, in which a primary\r\nbinding was proved to occur at the active gorge site, and a secondary binding was revealed at the peripheral anionic site. Structure\r\nactivity relationships of prepared compounds were also discussed....
The relationship between sequence polymorphisms and human disease has been studied mostly in terms of effects of\r\nsingle nucleotide polymorphisms (SNPs) leading to single amino acid substitutions that change protein structure and\r\nfunction. However, less attention has been paid to more drastic sequence polymorphisms which cause premature\r\ntermination of a protein�s sequence or large changes, insertions, or deletions in the sequence. We have analyzed a large set\r\n(n = 512) of insertions and deletions (indels) and single nucleotide polymorphisms causing premature termination of\r\ntranslation in disease-related genes. Prediction of protein-destabilization effects was performed by graphical presentation of\r\nthe locations of polymorphisms in the protein structure, using the Genomes TO Protein (GTOP) database, and manual\r\nannotation with a set of specific criteria. Protein-destabilization was predicted for 44.4% of the nonsense SNPs, 32.4% of the\r\nframeshifting indels, and 9.1% of the non-frameshifting indels. A prediction of nonsense-mediated decay allowed to infer\r\nwhich truncated proteins would actually be translated as defective proteins. These cases included the proteins linked to\r\ndiseases inherited dominantly, suggesting a relation between these diseases and toxic aggregation. Our approach would be\r\nuseful in identifying potentially aggregation-inducing polymorphisms that may have pathological effects....
Monoamine Oxidase (MAO) regulates monoamine neurotransmitters such as serotonin, dopamine and nor-adrenaline by oxidative deamination. MAO inhibitors are especially useful in treating people whose depression is combined with other problems such as anxiety, panic attacks, phobias, or the desire to sleep too much. Unfortunately the available drugs have serious side effects like ‘Cheese effect’ especially when taken with special foods, beverages etc. To ameliorate the situation the search can be focus on safer alternatives to the MAO’s. In this context we have identified novel ligand to target MAO-A isoform using target search options in zinc database. The docking analysis divulges that ligand zinc_667007 interact with MAO-A enzyme through hydrogen bonding, arene-cation interaction and nonbonding contacts. The analysis bring to a close that purine ring with carbonyl function plays imperative role, amide linkage added hydrogen bond acceptor feature, important for drug receptor interactions while terminal ethyl benzoate plays dual role as it was engaged in arene-cation as well as hydrogen bonding therefore enhance drug receptor interactions....
Exchange proteins directly activated by cAMP (EPACs) are important allosteric regulators of cAMP-mediated signal\r\ntransduction pathways. To understand the molecular mechanism of EPAC activation, we have combined site-directed\r\nmutagenesis, X-ray crystallography, and peptide amide hydrogen/deuterium exchange mass spectrometry (DXMS) to probe\r\nthe structural and conformational dynamics of EPAC2-F435G, a constitutively active EPAC2 mutant. Our study demonstrates\r\nthat conformational dynamics plays a critical role in cAMP-induced EPAC activation. A glycine mutation at 435 position\r\nshifts the equilibrium of conformational dynamics towards the extended active conformation....
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