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81.
Peter S. Kutchukian Nadya Y. Vasilyeva Jordan Xu Mika K. Lindvall Michael P. Dillon Meir Glick John D. Coley Natasja Brooijmans 《PloS one》2012,7(11)
Medicinal chemists’ “intuition” is critical for success in modern drug discovery. Early in the discovery process, chemists select a subset of compounds for further research, often from many viable candidates. These decisions determine the success of a discovery campaign, and ultimately what kind of drugs are developed and marketed to the public. Surprisingly little is known about the cognitive aspects of chemists’ decision-making when they prioritize compounds. We investigate 1) how and to what extent chemists simplify the problem of identifying promising compounds, 2) whether chemists agree with each other about the criteria used for such decisions, and 3) how accurately chemists report the criteria they use for these decisions. Chemists were surveyed and asked to select chemical fragments that they would be willing to develop into a lead compound from a set of ∼4,000 available fragments. Based on each chemist’s selections, computational classifiers were built to model each chemist’s selection strategy. Results suggest that chemists greatly simplified the problem, typically using only 1–2 of many possible parameters when making their selections. Although chemists tended to use the same parameters to select compounds, differing value preferences for these parameters led to an overall lack of consensus in compound selections. Moreover, what little agreement there was among the chemists was largely in what fragments were undesirable. Furthermore, chemists were often unaware of the parameters (such as compound size) which were statistically significant in their selections, and overestimated the number of parameters they employed. A critical evaluation of the problem space faced by medicinal chemists and cognitive models of categorization were especially useful in understanding the low consensus between chemists. 相似文献
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83.
Lounkine E Kutchukian P Petrone P Davies JW Glick M 《Bioorganic & medicinal chemistry》2012,20(18):5416-5427
The increasing amount of chemogenomics data, that is, activity measurements of many compounds across a variety of biological targets, allows for better understanding of pharmacology in a broad biological context. Rather than assessing activity at individual biological targets, today understanding of compound interaction with complex biological systems and molecular pathways is often sought in phenotypic screens. This perspective poses novel challenges to structure-activity relationship (SAR) assessment. Today, the bottleneck of drug discovery lies in the understanding of SAR of rich datasets that go beyond single targets in the context of biological pathways, potential off-targets, and complex selectivity profiles. To aid in the understanding and interpretation of such complex SAR, we introduce Chemotography (chemotype chromatography), which encodes chemical space using a color spectrum by combining clustering and multidimensional scaling. Rich biological data in our approach were visualized using spatial dimensions traditionally reserved for chemical space. This allowed us to analyze SAR in the context of target hierarchies and phylogenetic trees, two-target activity scatter plots, and biological pathways. Chemotography, in combination with the Kyoto Encyclopedia of Genes and Genomes (KEGG), also allowed us to extract pathway-relevant SAR from the ChEMBL database. We identified chemotypes showing polypharmacology and selectivity-conferring scaffolds, even in cases where individual compounds have not been tested against all relevant targets. In addition, we analyzed SAR in ChEMBL across the entire Kinome, going beyond individual compounds. Our method combines the strengths of chemical space visualization for SAR analysis and graphical representation of complex biological data. Chemotography is a new paradigm for chemogenomic data visualization and its versatile applications presented here may allow for improved assessment of SAR in biological context, such as phenotypic assay hit lists. 相似文献
84.
Xu X Vaithiyalingam S Glick GG Mordes DA Chazin WJ Cortez D 《Molecular and cellular biology》2008,28(24):7345-7353
ATR kinase activation requires the recruitment of the ATR-ATRIP and RAD9-HUS1-RAD1 (9-1-1) checkpoint complexes to sites of DNA damage or replication stress. Replication protein A (RPA) bound to single-stranded DNA is at least part of the molecular recognition element that recruits these checkpoint complexes. We have found that the basic cleft of the RPA70 N-terminal oligonucleotide-oligosaccharide fold (OB-fold) domain is a key determinant of checkpoint activation. This protein-protein interaction surface is able to bind several checkpoint proteins, including ATRIP, RAD9, and MRE11. RAD9 binding to RPA is mediated by an acidic peptide within the C-terminal RAD9 tail that has sequence similarity to the primary RPA-binding surface in the checkpoint recruitment domain (CRD) of ATRIP. Mutation of the RAD9 CRD impairs its localization to sites of DNA damage or replication stress without perturbing its ability to form the 9-1-1 complex or bind the ATR activator TopBP1. Disruption of the RAD9-RPA interaction also impairs ATR signaling to CHK1 and causes hypersensitivity to both DNA damage and replication stress. Thus, the basic cleft of the RPA70 N-terminal OB-fold domain binds multiple checkpoint proteins, including RAD9, to promote ATR signaling. 相似文献
85.
In the budding yeast Saccharomyces cerevisiae, mutations in the essential gene CDC1 cause defects in Golgi inheritance and actin polarization. However, the biochemical function of Cdc1p is unknown. Previous work showed that cdc1 mutants accumulate intracellular Ca(2+) and display enhanced sensitivity to the extracellular Mn(2+) concentration, suggesting that Cdc1p might regulate divalent cation homeostasis. By contrast, our data indicate that Cdc1p is a Mn(2+)-dependent protein that can affect Ca(2+) levels. We identified a cdc1 allele that activates Ca(2+) signaling but does not show enhanced sensitivity to the Mn(2+) concentration. Furthermore, our studies show that Cdc1p is an endoplasmic reticulum-localized transmembrane protein with a putative phosphoesterase domain facing the lumen. cdc1 mutant cells accumulate an unidentified phospholipid, suggesting that Cdc1p may be a lipid phosphatase. Previous work showed that deletion of the plasma membrane Ca(2+) channel Cch1p partially suppressed the cdc1 growth phenotype, and we find that deletion of Cch1p also suppresses the Golgi inheritance and actin polarization phenotypes. The combined data fit a model in which the cdc1 mutant phenotypes result from accumulation of a phosphorylated lipid that activates Ca(2+) signaling. 相似文献
86.
87.
Characterization of the Novel Fusobacterium nucleatum Plasmid pKH9 and Evidence of an Addiction System
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Gilad Bachrach Susan Kinder Haake Alon Glick Ronen Hazan Ronit Naor Roxanna N. Andersen Paul E. Kolenbrander 《Applied microbiology》2004,70(12):6957-6962
Fusobacterium nucleatum is an important oral anaerobic pathogen involved in periodontal and systemic infections. Studies of the molecular mechanisms involved in fusobacterial virulence and adhesion have been limited by lack of systems for efficient genetic manipulation. Plasmids were isolated from eight strains of F. nucleatum. The smallest plasmid, pKH9 (4,975 bp), was characterized and used to create new vectors for fusobacterial genetic manipulation. DNA sequence analysis of pKH9 revealed an open reading frame (ORF) encoding a putative autonomous rolling circle replication protein (Rep), an ORF predicted to encode a protein homologous to members of the FtsK/SpoIIIE cell division-DNA segregation protein family, and an operon encoding a putative toxin-antitoxin plasmid addiction system (txf-axf). Deletion analysis localized the pKH9 replication region in a 0.96-kbp fragment. The pKH9 rep gene is not present in this fragment, suggesting that pKH9 can replicate in fusobacteria independently of the Rep protein. A pKH9-based, compact Escherichia coli-F. nucleatum shuttle plasmid was constructed and found to be compatible with a previously described pFN1-based fusobacterial shuttle plasmid. Deletion of the pKH9 putative addiction system (txf-axf) reduced plasmid stability in fusobacteria, indicating its addiction properties and suggesting it to be the first plasmid addiction system described for fusobacteria. pKH9, its genetic elements, and its shuttle plasmid derivatives can serve as useful tools for investigating fusobacterial properties important in biofilm ecology and pathogenesis. 相似文献
88.
89.
D Glick Y Katsumata W A Skinner 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1975,149(3):763-765
The vitamin E analog, 2,2,7,8-tetramethyl-5,6-orthoquinonechroman, unlike vitamin E itself, had been reported to be a potent inhibitor of beef liver cyclic AMP-PDE in vitro (about 3.5 times more inhibitory than theophylline under the same conditions). In this in vivo study, single intraperitoneal injections were given to fasted rats, 15 min before killing, of a solution of 20, and of a suspension of 130, mg analog/kg in 4% ethanol. No significant increases over the 4% ethanol control values in cyclic AMP levels were produced in any of the histological regions of the glandular stomach. However, injection of the 4% ethanol itself produced a rise of about 50% (peak value 4.1 pmoles/mg wet wt, 0.16 pmoles/mug protein-nitrogen) in the cyclic AMP concentrations in the parietal cell region and had no significant effect in any of the other histological zones where the concentrations were much lower. 相似文献
90.