Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A method is presented for enumerating a large number of isosteric analogues of a ligand from a known protein-ligand complex structure and then rapidly calculating an estimate of their binding energies. This approach takes full advantage of the observed crystal structure, by reusing the atomic co-ordinates determined experimentally for one ligand, to approximate those of similar compounds that have approximately the same shape. By assuming that compounds with similar shapes adopt similar binding poses, and that entropic and protein flexibility effects are approximately constant across such an isosteric series ("the frozen ligand approximation"), it is possible to order their binding affinities relatively accurately. Additionally, the constraint that the atomic coordinates are invariant allows for a dramatic simplification in the Poisson-Boltzmann method used to calculation the electrostatic component of the binding energy. This algorithmic improvement allows for the calculation of tens of thousands of binding energies per second for drug-like molecules, enabling this technique to be used in screening large virtual libraries of isosteric analogues. Most significantly, this procedure is shown to be able to reproduce SAR effects of subtle medicinal chemistry substitutions. Finally, this paper reports the results of the proposed methodology on seven model systems; dihydrofolate reductase, Lck kinase, ribosome inactivating protein, L: -arabinose binding protein, neuraminidase, HIV-1 reverse transcriptase and COX-2.
J Comput Aided Mol Des 2006 Apr
PMID:Electrostatic evaluation of isosteric analogues. 1684 6

The polymerase chain reaction (PCR), which can exponentially replicate a target DNA sequence, has formed the basis for the sensitive and direct examination of clinical samples for evidence of infection. During the epidemic of severe acute respiratory syndrome (SARS) in 2003, PCR not only offered a rapid way to diagnose SARS-coronavirus (SARS-CoV) infection, but also made the molecular analysis of its genomic sequence possible. Sequence variations were observed in the SAR-CoV obtained from different patients in this epidemic. These unique viral genetic signatures can be applied as a powerful molecular tool in tracing the route of transmission and in studying the genome evolution of SARS-CoV. To extract this wealth of information from the limited primary clinical specimens of SARS patients, we were presented with the challenge of efficiently amplifying fragments of the SARS-CoV genome for analysis. In this chapter, we will discuss how we managed to accomplish this task with our optimized protocols on reverse-transcription, nested PCR amplification, and DNA cycle sequencing. We will also discuss the sequence variations that typified some strains of SARS-CoV in the different phases during this epidemic. PCR amplification of the viral sequence and genomic sequencing of these critical sequence variations of re-emerging SARS-CoV strains would give us quick insights into the virus.
Methods Mol Biol 2006
PMID:Genomic sequencing of the severe acute respiratory syndrome-coronavirus. 1691 63

It has been nearly ten years since the introduction of SAR by NMR and the advent of fragment-based drug design. During this time, we have gained a tremendous amount of knowledge about protein druggability, the limits of chemical diversity, and crafting high-affinity ligands from low molecular weight, weakly binding leads. This review will describe the concept of fragment-based drug design, discuss why it works, and illustrate the power of the approach with two case studies on the design of potent inhibitors of matrix metalloproteinases and Bcl-2 family proteins.
Mol Interv 2006 Oct
PMID:SAR by NMR: putting the pieces together. 1703 67

The first International Symposium on Cholinergic Mechanism (ISCM), organized by the late Edith Heilbronn, was held in Skokloster in 1970; Alicante's XII ISCM shows the exponential progress made in the cholinergic field in barely 30 years! Thus, Alzheimer's disease was not a topic at the first ISCM. The concept of homeostatic mechanisms regulating choline levels in the brain was not conceived of as yet. Three-dimensional pictures and the the protein structure of cholinergic receptors were not even thought of, as in 1970, we had only an "abstract" knowledge of receptors, based on SAR notions of Everhardus Ariens, Robert Furchgott, and Peter Pauling; in fact the Nobel Prize winner Furchgott stated in 1964 that "... with rare exceptions, we cannot ... identify the receptor as an individual chemical entity." Similarly, three-dimensional images of cholinesterases (ChEs) and the ChE "gorges" were unknown (Furchgott, 1964). The Whittakerian notion of synaptic vesicular release of acetylcholine (ACh) was the only version of the mode of ACh release, and the unorthodox opinions of Yves Dunant, Maurice Israel, Bruno Ceccarelli and Jacopo Meldolesi were still to be promulgated. Little was known about cholinergic correlates of behaviors such as learning and aggression, and there was no notion of cholinergic aspects of self-awareness (consciousness), free will, and the active subconscious. And modern methodologies were unknown, including the measurements of ACh, such as the gas chromatography-mass spectrometry (GCMS) method, discovered by Israel Hanin, Don Jenden, and Bo Holmstedt in the 1950s, the chemiluminescence developed by Maurice Israel, Yves Dunant, and their associates (Israel et al., 1983), and crystallography and molecular biology techniques, such as the "knockout" (KO) mouse models.
J Mol Neurosci 2006
PMID:Conclusions and comments for the XII ISCM. 1719 84

Extensive 3D-QSAR studies were performed on 158 diverse analogues of 3-pyridyl ethers, which are excellent ligands of alpha4beta2 neuronal nicotinic acetylcholine receptor (NnAChR). Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques were used to relate the binding affinities with the ligand structures. Two QSAR models were obtained using CoMFA and CoMSIA techniques. The two QSAR models were proved to be statistically significant and have high predictive power. The best CoMFA model yielded the cross-validated q(2)=0.605 and the non-cross-validated r(2)=0.862. The derived model indicated the importance of steric (85.9%) as well as electrostatic (14.1%) contributions. The CoMFA model demonstrated the steric field as the major descriptor of the ligand binding. The best CoMSIA model gave q(2)=0.723 and r(2)=0.685. This model showed that steric (30.3%) and H-bond interaction (61.8%) properties played major roles in ligand binding process. The squares of correlation coefficient for external test set of 28 molecules were 0.723 and 0.685 for the CoMFA model and the CoMSIA model, respectively. The two models were further graphically interpreted in terms of field contribution maps. SAR studies were also performed on different series of compounds in order to get a more reasonable understanding of the interactions between the ligands and the receptor. With the results, we have also presumed some assistant elements as supplements to the traditional pharmacophoric elements. A crude vision of ligand localization in the ligand-binding pocket of the receptor was also obtained, which would favor for the docking study of this kind of ligands.
J Mol Graph Model 2007 Jul
PMID:QSAR study of a large set of 3-pyridyl ethers as ligands of the alpha4beta2 nicotinic acetylcholine receptor. 1720 24

Based primarily on further studies of a collection of eleven publications reporting fifteen successful 3D-QSAR relations, several phenomena are preliminarily described. The RMS error of 133 ligand binding energy predictions based on these successful 3D-QSARs is 0.75 kcal/mole, which compares favorably to the prediction accuracies of approaches that include the receptor. A similar result is obtained when topomer alignments are substituted for those published, with seemingly profound implications for the future of 3D-QSAR. The "alignment-averaged" molecular properties, log P and molar refractivity, have very little correlative power for these data sets, either alone or in combination with the 3D-QSAR field descriptors. The q (2 )metric for the number of PLS components necessarily tends to discard any unique or unconfirmed SAR information. Large drops in q (2) are thus to be expected whenever such unique information is first encountered. Predictive r (2) values from an exploratory new "series trajectory" analysis of these 3D-QSAR though highly variable do not differ much from their q (2) values, a phenomenon that seems to encourage prediction even when there are so few structures underlying a 3D-QSAR so that almost all information is unique.
J Comput Aided Mol Des
PMID:Pushing the boundaries of 3D-QSAR. 1725 17

Effector proteins injected by the pathogenic bacteria Pseudomonas syringae into plants can have profound effects on the pathogen-host interaction due to their efficient recognition by plants and the subsequent triggering of defenses. The AvrRpt2 effector triggers strong local and systemic defense (called systemic acquired resistance [SAR]) responses in Arabidopsis thaliana plants that harbor a functional RPS2 gene that encodes an R protein in the coiled-coil, nucleotide-binding domain, leucine-rich repeat class. The newly identified win3-T mutant shows greatly reduced resistance to P syringae carrying avrRpt2. In win3-T plants, RIN4 cleavage, an early AvrRpt2-induced event, is normal. However, salicylic acid accumulation is compromised, as is SAR induction and the local hypersensitive cell death response after infection by P syringae carrying avrRpt2. WIN3 encodes a member of the firefly luciferase protein superfamily. Expression of WIN3 at an infection site partially requires PAD4, a protein known to play a quantitative role in RPS2-mediated signaling. WIN3 expression in tissue distal to an infection site requires multiple salicylic acid regulatory genes. Finally, win3-T plants show modestly increased susceptibility to virulent P syringae and modestly reduced SAR in response to P. syringae carrying avrRpm1. Thus, WIN3 is a key element of the RPS2 defense response pathway and a basal and systemic defense component.
Mol Plant Microbe Interact 2007 Oct
PMID:A key role for the Arabidopsis WIN3 protein in disease resistance triggered by Pseudomonas syringae that secrete AvrRpt2. 1791 21

Recently we constructed recombinant yeast cells that express the human androgen receptor (hAR) and yeast enhanced green fluorescent protein (yEGFP), the latter in response to androgens. When exposed to 17beta-testosterone, the concentration where half-maximal activation is reached (EC50) was 50 nM. Relative androgenic potencies (RAP), defined as the ratio between the EC50 of 17beta-testosterone and the EC50 of the compound, were 1.7, 1.2 and 0.008 for 19-nortestosterone, tetrahydrogestrinone and 17beta-estradiol respectively. Steroids representative for other hormone receptors, like estrone, 17alpha-ethynylestradiol, and diethylstilbestrol for the estrogen receptor and corticosterone and dexamethasone for the glucocorticoid receptor, showed no agonistic response. Only compounds known to exert androgenic effects give a response. Determined RAPs were in line with results obtained from optimised QSAR model calculations and demonstrated that Saccharomyces cerevisiae showed no metabolism of test compounds and displayed no crosstalk from endogenous hormone receptors. The suitability of this bioassay to verify the outcomes of (Q)SAR models to predict the activities of different steroids was further examined by studies with steroid isomers and a number of designer steroids, confirming that the 17beta-hydroxyl group, 3-keto group and 5alpha-steroidal framework are extremely important for the activity of the androgenic steroid.
J Steroid Biochem Mol Biol 2008 Jan
PMID:A new highly androgen specific yeast biosensor, enabling optimisation of (Q)SAR model approaches. 1794 80

In-silico models were generated to predict the extent of inhibition of cytochrome P450 isoenzymes using a set of relatively interpretable descriptors in conjunction with partial least squares (PLS) and regression trees (RT). The former was chosen due to the conservative nature of the resultant models built and the latter to more effectively account for any non-linearity between dependent and independent variables. All models are statistically significant and agree with the known SAR and they could be used as a guide to P450 liability through a classification based on the continuous pIC50 prediction given by the model. A compound is classified as having either a high or low P450 liability if the predicted pIC(50) is at least one root mean square error (RMSE) from the high/low pIC(50) cut-off of 5. If predicted within an RMSE of the cut-off we cannot be confident a compound will be experimentally low or high so an indeterminate classification is given. Hybrid models using bulk descriptors and fragmental descriptors do significantly better in modeling CYP450 inhibition, than bulk property QSAR descriptors alone.
J Comput Aided Mol Des
PMID:Generation of in-silico cytochrome P450 1A2, 2C9, 2C19, 2D6, and 3A4 inhibition QSAR models. 1803 11

Production of embryos in vitro has enormous potential for research and commercial applications. Unfortunately, in vitro production of porcine embryos is extremely inefficient. Despite the characterization of distinct phenotypes, little is known about the molecular mechanisms and altered physiological processes of in vitro-produced embryos. The objective of this study was to compare global gene expression patterns from in vivo- (IVO) and in vitro-produced (IVP) porcine embryos using small amplified RNA-serial analysis of gene expression (SAR-SAGE). Whole-cell RNA from pools of Day 6 IVO and IVP blastocysts was used to construct SAR-SAGE libraries. Sequence analysis of the IVO and IVP libraries yielded 98,771 and 98,408 tags, respectively. A total of 20,029 and 23,453 putative transcripts were detected in the IVO and IVP libraries, respectively. Statistical analyses of SAGE tag frequencies between the IVO and IVP libraries indicated that 938 and 193 tags were differentially expressed at a P < 0.05 and P < 0.001 level of significance, respectively, suggesting significant deviations in transcriptome profiles from IVO and IVP embryos. Categorization of differentially expressed transcripts into functional groupings indicated a significant deviation in gene expression from IVP blastocysts compared with IVO blastocysts for a number of biological processes including cellular metabolism, organization, and response to stress. Real-time PCR confirmed differential expression for several transcripts from independent IVO and IVP blastocysts. These results demonstrate compromised gene expression in IVP blastocysts compared with IVO blastocysts for a number of biological processes, particularly processes involved in mitochondrial function; thereby providing potential target pathways for improvement of IVP methods.
Mol Reprod Dev 2008 Jun
PMID:Comparative transcriptome analysis of in vivo- and in vitro-produced porcine blastocysts by small amplified RNA-serial analysis of gene expression (SAR-SAGE). 1835 60


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>