http://precedings.nature.com/tags/docking Recently posted documents tagged with 'docking' Nature Publishing Group en Nature Precedings http://precedings.nature.com/images/header_logo.gif http://precedings.nature.com http://precedings.nature.com/documents/3776/version/1 The emergence of tuberculosis resistant to multiple, first- and second-line antibiotics poses challenges to a global control strategy that relies on standard drug treatment regimens. The high drug-resistant strains of Mycobacterium tuberculosis (Mtb) have been implicated in outbreaks and have been found throughout the world; a comprehensive understanding, the magnitude of this threat requires an accurate assessment of the worldwide burden of resistance. In an attempt to design anti-TB drugs, the target chosen is a key enzyme of Mtb, O-Succinylbenzoate synthase (OSBS), which is an attractive target for its role in electron transport chain as OSBS is not available in humans. An attempt has been to built the 3-D structure of Mtb-OSBS using online Swiss model server. With sequence alignment and scan motif identification, the importance of evolutionarily significant residues that are of functional importance for ligand binding and that form active sites were well established. Molecular simulation calculations of Mtb-OSBS model indicated evolutionarily conserve residues (Lys110 and Lys212) are the best in molecular interaction with substrate 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC). The in silico mutational analysis of Mtb-OSBS model showed the evolutionarily conserved residues that are essential for catalytic activity. It has been found that active site amino acids of Mtb-OSBS are very important to maintain activity of the enzyme, which provides a novel approach to design new pharmacophore SHCHC substrate analogs against Mtb-OSBS. A series of SHCHC substrate analogs (1–100) compounds have been docked with the amino acid residues at the active site of the Mtb-OSBS enzyme, using AutoDock 4.0, a program employed to perform automated molecular docking. The free energies of binding (∆G) and inhibition constants (Ki) of the docked compounds were calculated by the Lamarckian Genetic Algorithm (LGA). Excellent to good correlations between the calculated and experimental Ki values were reported. http://precedings.nature.com/documents/3776/version/1 Fri, 18 Sep 2009 16:35:16 UTC Prediction of Evolutionarily important catalytic amino acid of Mycobacterium tuberculosis O-Succinylbenzoate synthase through in silico mutational analysis hdl:10101/npre.2009.3776.1 2009-09-18 Suresh Kumar Chitta Nature Precedings 2009-09-18T16:35:16Z Poster Biotechnology Microbiology Pharmacology Bioinformatics http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/3731/version/1 Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world’s population is infected with Mycobacterium tuberculosis (Mtb), the etiologic agent of TB. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and about two million deaths are attributable to TB annually. The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. In this work, 3D structural model of Mtb-MurA enzyme has been developed, for the first time, by homology modeling and molecular dynamics simulation techniques. The model provided clear insight in its structure features, i.e. substrate binding pocket, and common docking site. Multiple sequence alignment and 3D structure model provided the putative substrate binding pocket of Mtb-MurA with respect to E.coli MurA. This analysis was helpful in identifying the binding sites and molecular function of the MurA homologue. Molecular docking study was performed on this 3D structural model, using different classes of inhibitors like fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic acid derivatives T6361, T6362 and the results showed that the 5-sulfonoxyanthranilic acid derivatives is showed best interaction compared with other inhibitor, taking in to this we also design a new efficient analogs of T6361 and T6362 which are showed even better interaction with Mtb-MurA than the parental5-sulfonoxy-anthranilic acid derivatives. Further the comparative molecular electrostatic potential and cavity depth analysis of Mtb-MurA suggested several important differences in its substrate and inhibitor binding pocket. Such differences could be exploited in the future for designing of a more specific inhibitor for Mtb-MurA enzyme http://precedings.nature.com/documents/3731/version/1 Tue, 08 Sep 2009 08:23:00 UTC Computational binding mechanism of Mycobacterium tuberculosis UDP-NAG enolpyruvyl transferase (MurA) with inhibitors fosfomycin, cyclic disulfide analog RWJ-3981, pyrazolopyrimidine analog RWJ-110192, purine analog RWJ-140998, 5-sulfonoxy-anthranilic aci hdl:10101/npre.2009.3731.1 2009-09-08 Suresh Kumar Chitta Nature Precedings 2009-09-08T08:23:00Z Manuscript Biotechnology Microbiology Bioinformatics http://creativecommons.org/licenses/by/3.0/ http://precedings.nature.com/documents/3541/version/1 In this study, we investigated the regioselective binding mode of steroid molecules and structure requirements for steroid molecules for 16α-hydroxylation by Cytochrome P450-2C11. Docking study by using the homology Cytochrome P450-2C11 indicated that 16α-hydroxylation is favored with steroidal molecules possessing the following components, 1) a bent A-B ring configuration (5β-reduced), 2) C-3α-hydroxyl group, 3) C-17β-acetyl group, and 4) methyl group at both the C-18 and C-19. These respective steroid components requirements such as A-B ring configuration and functional groups at C-3 and C-17 were defined as the inhibitory contribution factor. Overall results by rat CYP2C11 revealed that steroidal structure requirements resulted in causing an effective inhibition of [3H]progesterone 16α-hydroxylation by the adult male rat liver microsome. As far as docking of homology modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16α-H was between 4 to 6 Å and that the related angle was in the range of 180±45°. http://precedings.nature.com/documents/3541/version/1 Mon, 03 Aug 2009 13:23:25 UTC Studies on Regioselective Binding Mode of Steroid Molecules in Homology Modeled Cytochrome P450-2C11 hdl:10101/npre.2009.3541.1 2009-08-03 Eiichi Akaho Nature Precedings 2009-08-03T13:23:25Z Manuscript Chemistry Bioinformatics http://creativecommons.org/licenses/by/3.0/ http://dx.doi.org/10.1038/npre.2007.1290.1 Human olfactory receptor, hOR17-210, is identified as a pseudogene in the human genome. Experimental data has shown however, that the gene product of cloned hOR17-210 cDNA was able to bind an odorant-binding protein and is narrowly tuned for excitation by cyclic ketones. Supported by experimental results, we used the bioinformatics methods of sequence analysis, computational protein modeling and docking, to show that functionality in this receptor is retained due to sequence-structure features not previously observed in mammalian ORs. This receptor does not possess the first two transmembrane helical domains (of seven typically seen in GPCRs). It however, possesses an additional TM that has not been observed in other human olfactory receptors. By incorporating these novel structural features, we created two putative models for this receptor. We also docked odor ligands that were experimentally shown to bind hOR17-210 model. We show how and why structural modifications of OR17-210 do not hinder this receptor’s functionality. Our studies reveal that novel gene rearrangement that result in sequence and structural diversity in has a bearing on OR and GPCR function and evolution. http://dx.doi.org/10.1038/npre.2007.1290.1 Mon, 05 Nov 2007 16:50:45 UTC An Olfactory Receptor Pseudogene whose Function emerged in Humans doi:10.1038/npre.2007.1290.1 2008-06-28 Chiquito J. Crasto Nature Precedings 2007-11-05T16:50:45Z Manuscript Biotechnology Neuroscience Bioinformatics http://creativecommons.org/licenses/by/2.5/ http://dx.doi.org/10.1038/npre.2007.52.1 The US FDA currently accepts carcinogenicity studies of pharmaceutical drugs based on murine models. In addition to 6 month studies with p53(+/-) and ras.H2 transgenic mice, lifetime studies (typically 2 years) in WT mice or rats are also considered as evidence that a drug lacks carcinogenic activity. This model is not always exhaustive. For example, during the acceptance testing of the ARB Olmesartan1, possible carcinogenicity observed in hamsters was not able to be duplicated in rats, or in transgenic mice. We have previously used the static molecular modeling of AutoDock to demonstrate that Olmesartan has agonostic activity in the PDB:1DB1 model of the human VDR Nuclear Receptor2, while it has antagonistic activity in the PDB:1RK3 model of the rat VDR. This agonism has now been confirmed with Molecular Dynamics, using GROMACS. The murine VDR indeed lost its ability to bind the DRIP-205 co-activator when Olmesartan was the ligand, while the human VDR was activated by Olmesartan similarly to its native ligand (1,25-dihydroxyvitamin-D). Since the VDR is believed to express 913 genes3, many of which are known to be associated with cancer pathogenesis, good homology between human VDR, and the animal model VDR, is exceedingly important. CONCLUSION: The murine environment is inadequate to accurately model drug carcinogenic activity in humans. A species should be chosen which has a VDR LBP homology closer to that of man. AutoDock and GROMACS molecular analyses are useful in resolving any remaining anomalies in the observed data.References:1. FDA CDER: NDA-21-286, Sankyo Pharma Inc Available from URL http://www.fda.gov/cder/foi/nda/2002/21-286_Benicar.htm2. Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract presentation, DMM2006.Available from URL http://AutoimmunityResearch.org/karolinska-handout.pdf3. Wang TT, et al: Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin-D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95. http://dx.doi.org/10.1038/npre.2007.52.1 Fri, 15 Jun 2007 15:05:40 UTC Molecular Static and Dynamic Analyses reveal Flaw in Murine Model used by US FDA to Detect Drug Carcinogenicity doi:10.1038/npre.2007.52.1 2007-06-15 Trevor Marshall Nature Precedings 2007-06-15T15:05:40Z Poster Biotechnology Cancer Immunology Pharmacology Bioinformatics http://creativecommons.org/licenses/by/2.5/