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Search Results: 1 - 10 of 15 matches for " Ekachai Jenwitheesuk "
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Improved prediction of HIV-1 protease-inhibitor binding energies by molecular dynamics simulations
Ekachai Jenwitheesuk, Ram Samudrala
BMC Structural Biology , 2003, DOI: 10.1186/1472-6807-3-2
Abstract: Docking experiments were undertaken using the program AutoDock for twenty-five HIV-1 protease-inhibitor complexes determined by x-ray crystallography. Protein-rigid docking without any dynamics produced a low correlation of 0.38 between the experimental and calculated binding energies. Correlations improved significantly for all time scales of MD simulations of the receptor-ligand complex. The highest correlation coefficient of 0.87 between the experimental and calculated energies was obtained after 0.1 picoseconds of dynamics simulation.Our results indicate that relaxation of protein complexes by MD simulation is useful and necessary to obtain binding energies that are representative of the experimentally determined values.The human immunodeficiency virus type 1 aspartic protease (HIV-1 PR) is an important enzyme due to its key role in viral maturation. Inactivation of the enzyme causes the production of immature, noninfectious viral particles. The enzyme therefore is an attractive target in anti-AIDS drug design, and the effect of binding various inhibitors on the protease structure is currently the focus of intensive research [1-3].To obtain information about the position and energy of binding between an inhibitor and the corresponding protein, several automated docking programs have been developed [4-6]. Given recent improvements in search algorithms and energy functions, computational docking methods have become a valuable tool to probe the interaction between an enzyme and its inhibitors. These methods can contribute significantly to the understanding of structural and energetic basis of enzyme-substrate interactions [7-9].Protein-ligand docking methods aim to predict the binding energy of the protein-ligand complex given the atomic coordinates. In such calculations, both the protein and ligand can be treated as rigid bodies [10,11]; alternately, the ligand, the protein, or both molecules, can be completely or partially flexible [12,13].One advantage of incorp
Homology modeling of mosquito cytochrome P450 enzymes involved in pyrethroid metabolism: insights into differences in substrate selectivity
Panida Lertkiatmongkol, Ekachai Jenwitheesuk, Pornpimol Rongnoparut
BMC Research Notes , 2011, DOI: 10.1186/1756-0500-4-321
Abstract: Homology models of the three An. minimus P450 enzymes were constructed using the multiple template alignment method. The predicted enzyme model structures were compared and used for molecular docking with insecticides and compared with results of in vitro enzymatic assays. The three model structures comprise common P450 folds but differences in geometry of their active-site cavities and substrate access channels are prominent. The CYP6AA3 model has a large active site allowing it to accommodate multiple conformations of pyrethroids. The predicted CYP6P7 active site is more constrained and less accessible to binding of pyrethroids. Moreover the predicted hydrophobic interface in the active-site cavities of CYP6AA3 and CYP6P7 may contribute to their substrate selectivity. The absence of CYP6P8 activity toward pyrethroids appears to be due to its small substrate access channel and the presence of R114 and R216 that may prevent access of pyrethroids to the enzyme heme center.Differences in active site topologies among CYPAA3, CYP6P7, and CYP6P8 enzymes may impact substrate binding and selectivity. Information obtained using homology models has the potential to enhance the understanding of pyrethroid metabolism and detoxification mediated by P450 enzymes.Insecticide resistance is a growing problem in the control of mosquito species that serve as vectors in the spread of malaria. One of the major classes of insecticide detoxification enzymes is the heme-containing cytochrome P450 monooxygenases (P450s). These enzymes are responsible for the metabolism of endogenous and exogenous compounds and the expression of several P450s is increased in insecticide resistant insects [1]. P450 enzymes are thought to promote resistance due to their ability to metabolize insecticidal compounds [2-5] however, the link between increased expression of P450s and insecticide resistance has not been clearly established. Structural information on insect P450s together with investigation of their
Pre-docking filter for protein and ligand 3D structures
Alisa Wilantho,Sissades Tongsima,Ekachai Jenwitheesuk
Bioinformation , 2008,
Abstract: Virtual drug screening using protein-ligand docking techniques is a time-consuming process, which requires high computational power for binding affinity calculation. There are millions of chemical compounds available for docking. Eliminating compounds that are unlikely to exhibit high binding affinity from the screening set should speed-up the virtual drug screening procedure. We performed docking of 6353 ligands against twenty-one protein X-ray crystal structures. The docked ligands were ranked according to their calculated binding affinities, from which the top five hundred and the bottom five hundred were selected. We found that the volume and number of rotatable bonds of the top five hundred docked ligands are similar to those found in the crystal structures and corresponded with the volume of the binding sites. In contrast, the bottom five hundred set contains ligands that are either too large to enter the binding site, or too small to bind with high specificity and affinity to the binding site. A pre-docking filter that takes into account shapes and volumes of the binding sites as well as ligand volumes and flexibilities can filter out low binding affinity ligands from the screening sets. Thus, the virtual drug screening procedure speed is increased.
Modeling of pyruvate decarboxylases from ethanol producing bacteria
Anjala Shrestha,Srisuda Dhamwichukorn,Ekachai Jenwitheesuk
Bioinformation , 2010,
Abstract: Pyruvate decarboxylase (PDC) is a key enzyme in homoethanol fermentation process, which decarboxylates 2-keto acid pyruvate into acetaldehyde and carbon dioxide. PDC enzymes from potential ethanol-producing bacteria such as Zymomonas mobilis, Zymobacter palmae and Sarcina ventriculi have different Km and kcat values for the substrate pyruvate at their respective optimum pH. In this study, the putative three-dimensional structures of PDC dimer of Z. palmae PDC and S. ventriculi PDC were generated based on the X-ray crystal structures of Z. mobilis PDC, Saccharomyces cerevisiae PDC form-A and Enterobacter cloacae indolepyruvate decarboxylase in order to compare the quaternary structures of these bacterial PDCs with respect to enzyme-substrate interactions, and subunit-subunit interfaces that might be related to the different biochemical characteristics. The PROCHECK scores for both models were within recommended intervals. The generated models are similar to the X-ray crystal structure of Z. mobilis PDC in terms of binding modes of the cofactor, the position of Mg2+, and the amino acids that form the active sites. However, subunit-subunit interface analysis showed lower H-bonding in both models compared with X-ray crystal structure of Z. mobilis PDC, suggesting a smaller interface area and the possibility of conformational change upon substrate binding in both models. Both models have predicted lower affinity towards branched and aromatic 2-keto acids, which correlated with the molecular volumes of the ligands. The models shed valuable information necessary for further improvement of PDC enzymes for industrial production of ethanol and other products.
Molecular dynamics simulation of a human thiopurine S-methyltransferase complexed with 6-mercaptopurine model
Wanwimon Mokmak,Sissades Tongsima,Ekachai Jenwitheesuk
Bioinformation , 2009,
Abstract: Human thiopurine S-methyltransferase (TPMT) is an essential protein in 6-mercaptopurine (6MP) drug metabolism. To understand the pharmacogenetics of TPMT and 6MP, X-ray co-crystal structures of TPMT complexes with S-adenosyl-L-methionine (AdoMet) and 6MP are required. However, the co-crystal structure of this complex has not been reported because 6MP is poorly water soluble. We used molecular dynamics (MD) simulation to predict the structure of the complex of human TPMT-AdoHcy(CH2)6MP, where the sulfur atoms of AdoHcy and 6MP were linked by a CH2 group. After 1300 picoseconds of MD simulation, the trajectory showed that 6MP was stabilized in the TPMT active site by formation of non-bonded interactions between 6MP and Phe40, Pro196 and Arg226 side chains of TPMT. The intersulfur distance between AdoHcy and 6MP as well as the binding modes and the interactions of our TPMT-AdoHcy model are consistent with those observed in the X-ray crystal structure of murine TPMT-AdoHcy-6MP complex. The predicted binding modes of AdoHcy and 6MP in our model are consistent with those observed in murine TPMT X-ray crystal structures, which provides structural insights into the interactions of TPMT, AdoHcy, and 6MP at the atomic level and may be used as a starting point for further study of thiopurine drug pharmacogenetics.
Prevalence of genotypic HIV-1 drug resistance in Thailand, 2002
Ekachai Jenwitheesuk, Chotip Watitpun, Asda Vibhagool, Wasun Chantratita
Annals of Clinical Microbiology and Antimicrobials , 2003, DOI: 10.1186/1476-0711-2-4
Abstract: Genotypic resistance testing was performed on samples collected in 2002 from 88 HIV-1 infected individuals. Automated DNA sequencing was used to genotype the HIV-1 polymerase gene isolated from patients' plasma.Resistance to protease inhibitors, nucleoside and non-nucleoside reverse transcriptase inhibitors were found in 10 (12%), 42 (48%) and 19 (21%) patients, respectively. The most common drug resistance mutations in the protease gene were at codon 82 (8%), 90 (7%) and 54 (6%), whereas resistant mutations at codon 215 (45%), 67 (40%), 41 (38%) and 184 (27%) were commonly found in the RT gene. This finding indicates that genotypic resistance to nucleoside reverse transcriptase inhibitors was prevalent in 2002. The frequency of resistant mutations corresponding to non-nucleoside reverse transcriptase inhibitors was three times higher-, while resistant mutation corresponding to protease inhibitors was two times lower than those frequencies determined in 2001.This study shows that the frequencies of RT inhibitor resistance mutations have been increased after the reduction in the price of RT inhibitors since December 2001. We believe that this was an important factor that influenced the mutation patterns of HIV-1 protease and RT genes in Thailand.During the last decade, the prevalence of human immunodeficiency virus type 1 (HIV-1) drug resistance has increased in developed countries as a result of widespread antiretroviral therapy [1-9]. Genotypic evidence of resistance for any drug was found in fewer than 2% of cases in one study from 1989 [4], increased to 10%-16% in cohorts recruited after 1995 [2,3], and attained between 20% and 26% in studies performed since 1997 [5-9]. Overall, several studies show rates of primary genotypic drug resistance between 10% and 18% for nucleoside reverse transcriptase inhibitors (NRTIs), of none to 13% for non-nucleoside reverse transcriptase inhibitors (NNRTIs), and of 3% to 7% for protease inhibitors (PIs) [1-9].In July 2002, S Sir
Structural Optimization and De Novo Design of Dengue Virus Entry Inhibitory Peptides
Joshua M. Costin,Ekachai Jenwitheesuk,Shee-Mei Lok,Elizabeth Hunsperger,Kelly A. Conrads,Krystal A. Fontaine,Craig R. Rees,Michael G. Rossmann,Sharon Isern,Ram Samudrala ,Scott F. Michael
PLOS Neglected Tropical Diseases , 2010, DOI: 10.1371/journal.pntd.0000721
Abstract: Viral fusogenic envelope proteins are important targets for the development of inhibitors of viral entry. We report an approach for the computational design of peptide inhibitors of the dengue 2 virus (DENV-2) envelope (E) protein using high-resolution structural data from a pre-entry dimeric form of the protein. By using predictive strategies together with computational optimization of binding “pseudoenergies”, we were able to design multiple peptide sequences that showed low micromolar viral entry inhibitory activity. The two most active peptides, DN57opt and 1OAN1, were designed to displace regions in the domain II hinge, and the first domain I/domain II beta sheet connection, respectively, and show fifty percent inhibitory concentrations of 8 and 7 μM respectively in a focus forming unit assay. The antiviral peptides were shown to interfere with virus:cell binding, interact directly with the E proteins and also cause changes to the viral surface using biolayer interferometry and cryo-electron microscopy, respectively. These peptides may be useful for characterization of intermediate states in the membrane fusion process, investigation of DENV receptor molecules, and as lead compounds for drug discovery.
Consistent association between beta DNA element and transfer RNA genes in Candida albicans
Ekachai Chukeatirote
Songklanakarin Journal of Science and Technology , 2004,
Abstract: In this study, the database of Candida albicans genome was screened to investigate the relationship between tRNA genes and retrotransposons. The results showed that, among 34 distinct families of LTR retrotransposons identified, only the beta element appeared to preferentially integrate near the tRNA genes. Specific site selection of the beta LTRs may be arisen from a coevolution process in which the host’s genome used to control their transposition. It is possible that, due to this coevolution mechanism, integration of the beta elements become mutualistic, although not proven, to the C. albicans genome by acting as a modulator in tRNA gene transcription.
Consistent association between beta DNA element and transfer RNA genes in Candida albicans
Ekachai Chukeatirote
Songklanakarin Journal of Science and Technology , 2005,
Abstract: The database of Candida albicans genome was screened to investigate the relationship between tRNA genes and retrotransposons. The results showed that, among 34 distinct families of LTR retrotransposons identified, only the beta element appeared to preferentially integrate near the tRNA genes. Specific site selection of the beta LTRs may have arisen from a coevolution process in which the host’s genome used to control their transposition. It is possible that, due to this coevolution mechanism, integration of the beta elements become mutualistic, although not proven, to the C. albicans genome by acting as a modulator in tRNA gene transcription.
Potential use of probiotics
Ekachai Chukeatirote
Songklanakarin Journal of Science and Technology , 2003,
Abstract: Probiotics (Greek: for life) are commonly defined as mono- or mixed cultures of live microbes that, when applied to animal or human, possess a beneficial effect on health of the host. These beneficial effects include disease treatment and prevention as well as improvement of nutrients’ digestion and absorption. Probiotic microorganisms are generally, albeit not exclusively, lactic acid bacteria (LAB) including Lactobacillus acidophilus, L. bulgaricus, L. casei, L. plantarum, and L. rhamnosus. However, use of other bacterial species such as Bacillus and Bifidobacterium spp. as probiotic strains has also been described in several commercial products. This article intends to present an up-to-date version regarding probiotics, strains currently used and health benefit obtained from their consumption.
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