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971.
A major goal in ligand and drug design is the optimization of the binding affinity of selected lead molecules. However, the binding affinity is defined by the free energy of binding, which, in turn, is determined by the enthalpy and entropy changes. Because the binding enthalpy is the term that predominantly reflects the strength of the interactions of the ligand with its target relative to those with the solvent, it is desirable to develop ways of predicting enthalpy changes from structural considerations. The application of structure/enthalpy correlations derived from protein stability data has yielded inconsistent results when applied to small ligands of pharmaceutical interest (MW < 800). Here we present a first attempt at an empirical parameterization of the binding enthalpy for small ligands in terms of structural information. We find that at least three terms need to be considered: (1) the intrinsic enthalpy change that reflects the nature of the interactions between ligand, target, and solvent; (2) the enthalpy associated with any possible conformational change in the protein or ligand upon binding; and, (3) the enthalpy associated with protonation/deprotonation events, if present. As in the case of protein stability, the intrinsic binding enthalpy scales with changes in solvent accessible surface areas. However, an accurate estimation of the intrinsic binding enthalpy requires explicit consideration of long-lived water molecules at the binding interface. The best statistical structure/enthalpy correlation is obtained when buried water molecules within 5-7 A of the ligand are included in the calculations. For all seven protein systems considered (HIV-1 protease, dihydrodipicolinate reductase, Rnase T1, streptavidin, pp60c-Src SH2 domain, Hsp90 molecular chaperone, and bovine beta-trypsin) the binding enthalpy of 25 small molecular weight peptide and nonpeptide ligands can be accounted for with a standard error of +/-0.3 kcal x mol(-1). 相似文献
972.
Chigo Anota E Bautista Hernández A Castro M Hernández Cocoletzi G 《Journal of molecular modeling》2012,18(5):2147-2152
Using first-principles total energy calculations within the density functional theory (DFT), we investigated the electronic and structural properties of graphene-like silicon sheets. Our studies were performed using the LSDA (PWC) and GGS (PBE) approaches. Two configurations were explored: one corresponding to a defect-free layer (h-Si), and the other to a layer with defects (d-Si), both of which were in the armchair geometry. These sheets contained clusters of the C(n)H(m) type. We also investigated the effects of doping with group IV-A elements. Structural stability was studied by only considering positive vibration frequencies. Results showed that both h-Si and d-Si present a corrugated structure with concavity. h-Si sheets were found to be ionic (D.M. = 0.33 Debye) with an energy gap (HOMO-LUMO) of 0.77 eV in the LSDA theory and 0.76 eV in the GGS approach, while d-Si sheets were observed to be covalent (D.M. = 2.78 D), and exhibited semimetallic electronic behavior (HOMO-LUMO gap = 0.32 eV within the LSDA theory and 0.33 eV within the GGS approach). d-Si sheets doped with one carbon or one germanium preserved the polarity of the undoped d-Si sheets, as well as their semimetallic electronic behavior. However, when the sheets were doped with two C or two Ge atoms, or with one of each atom (to give Si(52)CGeH(18)), they retained the semimetallic behavior, but they changed from having ionic character to covalent character. 相似文献
973.
Sho Konno Pillaiyar Thanigaimalai Takehito Yamamoto Kiyohiko Nakada Rie Kakiuchi Kentaro Takayama Yuri Yamazaki Fumika Yakushiji Kenichi Akaji Yoshiaki Kiso Yuko Kawasaki Shen-En Chen Ernesto Freire Yoshio Hayashi 《Bioorganic & medicinal chemistry》2013,21(2):412-424
We describe here the design, synthesis and biological evaluation of a series of molecules toward the development of novel peptidomimetic inhibitors of SARS-CoV 3CLpro. A docking study involving binding between the initial lead compound 1 and the SARS-CoV 3CLpro motivated the replacement of a thiazole with a benzothiazole unit as a warhead moiety at the P1′ site. This modification led to the identification of more potent derivatives, including 2i, 2k, 2m, 2o, and 2p, with IC50 or Ki values in the submicromolar to nanomolar range. In particular, compounds 2i and 2p exhibited the most potent inhibitory activities, with Ki values of 4.1 and 3.1 nM, respectively. The peptidomimetic compounds identified through this process are attractive leads for the development of potential therapeutic agents against SARS. The structural requirements of the peptidomimetics with potent inhibitory activities against SARS-CoV 3CLpro may be summarized as follows: (i) the presence of a benzothiazole warhead at the S1′-position; (ii) hydrogen bonding capabilities at the cyclic lactam of the S1-site; (iii) appropriate stereochemistry and hydrophobic moiety size at the S2-site and (iv) a unique folding conformation assumed by the phenoxyacetyl moiety at the S4-site. 相似文献
974.
Laura Lazo Alienys Izquierdo Edith Suzarte Lázaro Gil Iris Valdés Ernesto Marcos Mayling Álvarez Yaremis Romero María Guadalupe Guzmán Gerardo Guillén Lisset Hermida Cruz 《Microbiology and immunology》2014,58(4):219-226
A dengue vaccine must induce protective immunity against the four serotypes of the virus. Our group has developed chimeric proteins consisting of the protein P64k from Neisseria meningitidis and the domain III from the four viral envelope proteins. In this study, the immunogenicity of a tetravalent vaccine formulation using aluminum hydroxide as adjuvant was evaluated in mice. After three doses, neutralizing antibody titers were detected against the four viral serotypes, the lowest seroconversion rate being against dengue virus serotype 4. One month after the last dose, immunized animals were challenged with infective virus, and partial but statistically significant protection was found to have been achieved. Based on these results, further studies in mice and non‐human primates using this tetravalent formulation in a prime‐boost strategy with attenuated viruses are strongly recommended. 相似文献
975.
Maria N. Gadaleta Anna M. Giuffrida Marcella Renis Ida Serra Giovanna Del Prete Ernesto Geremia Cecilia Saccone 《Neurochemical research》1979,4(1):25-35
DNA, RNA, and protein synthesis in mitochondria isolated from cerebral hemispheres, brain stem, and cerebellum of 10- and 30-day-old rats was measured. Synthesis of different macromolecules was affected by the respective mitochondrial specific inhibitors, showing a good level of purity of mitochondrial preparations. DNA and protein synthesis in 10-day-old rats was about 70% higher than in 30-day-old animals. In contrast, RNA synthesis did not decrease with age in all the regions examined. 相似文献
976.
Khen Khermesh Anna Maria D'Erchia Michal Barak Anita Annese Chaim Wachtel Erez Y. Levanon Ernesto Picardi Eli Eisenberg 《RNA (New York, N.Y.)》2016,22(2):290-302
Adenosine to inosine (A-to-I) RNA editing, catalyzed by the ADAR enzyme family, acts on dsRNA structures within pre-mRNA molecules. Editing of the coding part of the mRNA may lead to recoding, amino acid substitution in the resulting protein, possibly modifying its biochemical and biophysical properties. Altered RNA editing patterns have been observed in various neurological pathologies. Here, we present a comprehensive study of recoding by RNA editing in Alzheimer''s disease (AD), the most common cause of irreversible dementia. We have used a targeted resequencing approach supplemented by a microfluidic-based high-throughput PCR coupled with next-generation sequencing to accurately quantify A-to-I RNA editing levels in a preselected set of target sites, mostly located within the coding sequence of synaptic genes. Overall, editing levels decreased in AD patients’ brain tissues, mainly in the hippocampus and to a lesser degree in the temporal and frontal lobes. Differential RNA editing levels were observed in 35 target sites within 22 genes. These results may shed light on a possible association between the neurodegenerative processes typical for AD and deficient RNA editing. 相似文献
977.
Pereira RC Stadmeyer L Marciniak SJ Ron D Canalis E 《Journal of cellular biochemistry》2006,97(3):633-640
C/EBP homologous protein (CHOP) suppresses adipogenesis and accelerates osteoblastogenesis in vitro. However, the effects of CHOP in the skeleton in vivo are not known. To investigate the actions of CHOP on bone remodeling, we examined the skeletal phenotype of chop null mice from 1 to 12 months of age. Chop null mice appeared normal and their growth and serum insulin like growth factor (IGF) I and osteocalcin levels were normal. X-ray analysis of the skeleton revealed no abnormalities and bone mineral density was normal. Static and dynamic histomorphometry revealed that chop null mice had decreased bone formation rates, without changes in osteoblast cell number, indicating an osteoblastic functional defect. The number of osteoblasts and osteoclasts and eroded surface were normal. Northern blot analysis revealed decreased type I collagen and osteocalcin mRNA levels in calvariae of chop null mice. In conclusion, chop null mice exhibit decreased bone formation and impaired osteoblastic function, indicating that CHOP is necessary for the normal expression of the osteoblastic phenotype. 相似文献
978.
979.
Despite its importance for the understanding of element cycles in ecosystems, organic matter (OM) quality has remained an elusive property that is difficult to measure. In this study, two new approaches, both of which taking into account the complete biochemical composition of the organic material during the decomposition process, have been combined to solve this problem. First, following the continuous-quality theory where quality is defined as a measure of substrate availability to the decomposers, initial litter OM qualities of a range of plant species from two experiments on litter decomposition were estimated and resulted in highly accurate fits of observed mass loss during decomposition. Applying the same theory, qualities of the litters at all stages of decomposition were then calculated. By comparison, the initial qualities of the same litters were estimated from conventional chemical fractions and resulted in much lower accurate fits. Second, near-infrared reflectance spectroscopy (NIRS), a highly precise physical method of characterising biochemical composition of OM, was used to obtain a unique spectral signature of each sample. Calibrations were performed between spectral data and calculated qualities on the first half of the sample set and the calibration equations were applied to the second half of the sample set. Results show that theoretical litter OM quality can be calibrated and predicted precisely using NIRS. OM quality, defined according to a theoretical concept of substrate availability to decomposers, then contains and summarises all the relevant biochemical information. We demonstrate how the combination of NIRS and theory allows us to accurately measure OM quality. Measurement of OM quality provides an access to a fundamental property of organic matter and opens up new possibilities for studying element cycles in ecosystems. 相似文献
980.