Abstract:
:Fragment screens for new ligands have had wide success, notwithstanding their constraint to libraries of 1,000-10,000 molecules. Larger libraries would be addressable were molecular docking reliable for fragment screens, but this has not been widely accepted. To investigate docking's ability to prioritize fragments, a library of >137,000 such molecules were docked against the structure of beta-lactamase. Forty-eight fragments highly ranked by docking were acquired and tested; 23 had K(i) values ranging from 0.7 to 9.2 mM. X-ray crystal structures of the enzyme-bound complexes were determined for 8 of the fragments. For 4, the correspondence between the predicted and experimental structures was high (RMSD between 1.2 and 1.4 A), whereas for another 2, the fidelity was lower but retained most key interactions (RMSD 2.4-2.6 A). Two of the 8 fragments adopted very different poses in the active site owing to enzyme conformational changes. The 48% hit rate of the fragment docking compares very favorably with "lead-like" docking and high-throughput screening against the same enzyme. To understand this, we investigated the occurrence of the fragment scaffolds among larger, lead-like molecules. Approximately 1% of commercially available fragments contain these inhibitors whereas only 10(-7)% of lead-like molecules do. This suggests that many more chemotypes and combinations of chemotypes are present among fragments than are available among lead-like molecules, contributing to the higher hit rates. The ability of docking to prioritize these fragments suggests that the technique can be used to exploit the better chemotype coverage that exists at the fragment level.
journal_name
Proc Natl Acad Sci U S Aauthors
Teotico DG,Babaoglu K,Rocklin GJ,Ferreira RS,Giannetti AM,Shoichet BKdoi
10.1073/pnas.0813029106subject
Has Abstractpub_date
2009-05-05 00:00:00pages
7455-60issue
18eissn
0027-8424issn
1091-6490pii
0813029106journal_volume
106pub_type
杂志文章abstract::The nucleotide sequences of eight origin-defective mutants of simian virus 40 have been determined. All of the mutants have suffered deletions, which range in size from 4 to 241 nucleotides. Some of the mutants induce the synthesis of tumor (T) antigen, others do not. Viral mRNA extracted from rat cells transformed by...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Measles virus (MeV) is the poster child for acute infection followed by lifelong immunity. However, recent work shows the presence of MeV RNA in multiple sites for up to 3 mo after infection in a proportion of infected children. Here, we use experimental infection of rhesus macaques to show that prolonged RNA presence...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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abstract::Nitric oxide (NO) biology has focused on the tightly regulated enzymatic mechanism that transforms L-arginine into a family of molecules, which serve both signaling and defense functions. However, very little is known of the pathways that metabolize these molecules or turn off the signals. The paradigm is well exempli...
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abstract::Palmitoylation is a common lipid modification known to regulate the functional properties of various proteins and is a vital step in the biosynthesis of voltage-activated sodium (Nav) channels. We discovered a mutation in an intracellular loop of rNav1.2a (G1079C), which results in a higher apparent affinity for exter...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2011-12-13 00:00:00
abstract::SoxR is a transcription factor that governs a global defense against the oxidative stress caused by nitric oxide or excess superoxide in Escherichia coli. SoxR is a homodimer containing a pair of [2Fe-2S] clusters essential for its transcriptional activity, and changes in the stability of these metal centers could con...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::1-Aminocyclopropane-1-carboxylate (ACC) oxidase catalyzes the oxidation of ACC to ethylene. Following conventional column fractionation, the enzyme was purified 180-fold to near homogeneity with a specific activity of 20 nmol/(mg.min). This purified enzyme preparation migrated as a single protein band with an apparent...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:1986-12-01 00:00:00
abstract::We have sequenced the mutant beta-actin gene of a tumorigenic human fibroblast cell line (HuT-14T) and found that it carries three mutations that alter the amino acids at positions 36, 83, and 244 as well as a 22-base-pair "insertion" sequence, in the 5' intron, not present in a wild-type gene. The less tumorigenic ce...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1985-10-01 00:00:00
abstract::Zeatin is the most active and ubiquitous of the naturally occurring cytokinins. The O-glucoside of zeatin, found in all plants examined, is considered to be important in cytokinin transport, storage, and protection against cytokinin oxidases. The enzyme UDPglucose:zeatin O-glucosyltransferase (EC 2.4.1.203) was previo...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1999-01-05 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1990-11-01 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1424111112
更新日期:2015-02-03 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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abstract::Sonic hedgehog (Shh) plays an integral role in both the anterior-posterior (A-P) patterning and expansion of developing vertebrate limbs through a feedback loop involving Fgfs, Bmps, and Gremlin. In bat limbs A-P patterning and the size of the digital field are unique. The posterior digits of the forelimb are elongate...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章,评审
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abstract::Ablation of inhibitory agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus that also synthesize gamma-amino-butyric acid (GABA) and neuropeptide Y in adult mice leads to starvation within 1 week. The removal of inhibition from the AgRP neurons onto neighboring proopiomelanocortin neurons and their ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2008-02-19 00:00:00
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2004-08-17 00:00:00
abstract::Our recent demonstration that many eukaryotic mRNAs contain sequences complementary to rRNA led to the hypothesis that these sequences might mediate specific interactions between mRNAs and ribosomes and thereby affect translation. In the present experiments, the ability of complementary sequences to bind to rRNA was i...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1998-10-13 00:00:00
abstract::The fluorescence decay of the rare earth terbium when bound to the protein calmodulin changes from a simple exponential decay to a complex nonexponential decay as the temperature is lowered below 200 K. We have fit the observed decay curves by assuming that the terbium emission is a forced electric dipole transition a...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:2006-02-21 00:00:00
abstract::Four new members of the fibroblast growth factor (FGF) family, referred to as fibroblast growth factor homologous factors (FHFs), have been identified by a combination of random cDNA sequencing, data base searches, and degenerate PCR. Pairwise comparisons between the four FHFs show between 58% and 71% amino acid seque...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1996-09-03 00:00:00
abstract::Bovine pyruvate dehydrogenase phosphatase (PDP) is a Mg2+-dependent and Ca2+-stimulated heterodimer that is a member of the protein phosphatase 2C family and is localized to mitochondria. Insight into the function of the regulatory subunit of PDP (PDPr) has been gained. It decreases the sensitivity of the catalytic su...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
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更新日期:1996-05-14 00:00:00
abstract::Liver fibrosis interferes with normal liver function and facilitates hepatocellular carcinoma (HCC) development, representing a major threat to human health. Here, we present a comprehensive perspective of microRNA (miRNA) function on targeting the fibrotic microenvironment. Starting from a murine HCC model, we identi...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:2020-01-07 00:00:00
abstract::Changes in the secondary structure of some dozen different proteins upon lyophilization of their aqueous solutions have been investigated by means of Fourier-transform infrared spectroscopy in the amide III band region. Dehydration markedly (but reversibly) alters the secondary structure of all the proteins studied, a...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
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更新日期:1995-11-21 00:00:00