Abstract：
:The rise of antibiotic resistance threatens modern medicine; to combat it new diagnostic methods are required. Sequencing the whole genome of a pathogen offers the potential to accurately determine which antibiotics will be effective to treat a patient. A key limitation of this approach is that it cannot classify rare or previously unseen mutations. Here we demonstrate that alchemical free energy methods, a well-established class of methods from computational chemistry, can successfully predict whether mutations in Staphylococcus aureus dihydrofolate reductase confer resistance to trimethoprim. We also show that the method is quantitatively accurate by calculating how much the most common resistance-conferring mutation, F99Y, reduces the binding free energy of trimethoprim and comparing predicted and experimentally measured minimum inhibitory concentrations for seven different mutations. Finally, by considering up to 32 free energy calculations for each mutation, we estimate its specificity and sensitivity.
journal_name
Cell Chem Bioljournal_title
Cell chemical biologyauthors
Fowler PW,Cole K,Gordon NC,Kearns AM,Llewelyn MJ,Peto TEA,Crook DW,Walker ASdoi
10.1016/j.chembiol.2017.12.009subject
Has Abstractpub_date
2018-03-15 00:00:00pages
339-349.e4issue
3eissn
2451-9456issn
2451-9448pii
S2451-9456(17)30437-3journal_volume
25pub_type
杂志文章abstract：:Recent advances in induced pluripotent stem cell technologies and phenotypic screening shape the future of bioactive small-molecule discovery. In this review we analyze the impact of small-molecule phenotypic screens on drug discovery as well as on the investigation of human development and disease biology. We further...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2019.05.007
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abstract：:Sirtuins are a large enzyme family involved in installing and removing post-translational modifications involving lysine side chains. These enzymes have been of intense research interest and we now understand many details of their mechanism, although later steps of the deacetylase activity have remained a mystery. In ...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2017.03.004
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abstract：:The rapid emergence of extensively drug-resistant A. baumannii has posed a major threat to global public health, emphasizing the desperate need for novel therapeutic strategies. We report the development of a highly efficient genome-engineering platform in A. baumannii by coupling a Cas9 nuclease-mediated genome cleav...
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abstract：:The glycan ligands recognized by Siglecs, influenza viruses, and galectins, as well as many plant lectins, are not well defined. To explore their binding to asparagine (Asn)-linked N-glycans, we synthesized a library of isomeric multiantennary N-glycans that vary in terminal non-reducing sialic acid, galactose, and N-...
journal_title：Cell chemical biology
pub_type： 杂志文章
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abstract：:G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel singl...
journal_title：Cell chemical biology
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abstract：:Contrary to the classic model of protein kinase A (PKA) residing outside of the nucleus, we identify a nuclear signaling complex that consists of AKAP95, PKA, and PDE4D5 and show that it forms a functional cyclic AMP (cAMP) signaling microdomain. Locally generated cAMP can accumulate within the vicinity of this comple...
journal_title：Cell chemical biology
pub_type： 杂志文章
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abstract：:Latency is the primary barrier to the development of a long-sought cure for HIV-1. In this issue of Cell Chemical Biology, Marian et al., (2018) describe the development of novel compounds targeting the BAF chromatin remodeling complex to reverse HIV latency, with the potential to provide a functional cure. ...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2018.12.007
更新日期：2018-12-20 00:00:00
abstract：:The unique photophysical properties of lanthanides, such as europium, terbium, and ytterbium, make them versatile molecular probes of biological systems. In particular, their long-lived photoluminescence, narrow bandwidth emissions, and large Stokes shifts enable experiments that are infeasible with organic fluorophor...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
doi：10.1016/j.chembiol.2020.07.009
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abstract：:In this issue of Cell Chemical Biology,De Cesare et al. (2018) report the development of a high-throughput assay that measures E2/E3 enzyme activity by MALDI-TOF mass spectrometry and apply this to screen for small molecule E3 inhibitors. This assay potentially accelerates the drug discovery for the ubiquitin ligation...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2018.09.002
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abstract：:Interfacial inhibitors exert their biological effects through co-association with two macromolecules. The pateamine A (PatA) class of molecules function by stabilizing eukaryotic initiation factor (eIF) 4A RNA helicase onto RNA, resulting in translation initiation inhibition. Here, we present the crystal structure of ...
journal_title：Cell chemical biology
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journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.02.010
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abstract：:In the nematode Caenorhabditis elegans, inactivating mutations in the insulin/IGF-1 receptor, DAF-2, result in a 2-fold increase in lifespan mediated by DAF-16, a FOXO-family transcription factor. Downstream protein activities that directly regulate longevity during impaired insulin/IGF-1 signaling (IIS) are poorly ch...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.06.015
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abstract：:In this issue of Cell Chemical Biology, Radlinski et al. (2019) identify Pseudomonas-derived rhamnolipids that potentiate aminoglycoside antibiotics in the eradication of antibiotic-tolerant bacterial phenotypes. Microbial physiological and mechanistic studies indicate that rhamnolipids permeabilize S. aureus membrane...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2019.09.015
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abstract：:In a recent issue of Cell Systems, Forcina et al. (2017) developed a scalable time-lapse analysis of cell death kinetics (STACK) method and combined it with a "lag exponential death" model to quantitatively characterize the onset and rate of cell death. STACK provides a useful quantitative tool to determine how cell d...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
doi：10.1016/j.chembiol.2017.07.006
更新日期：2017-07-20 00:00:00
abstract：:Chemical strategies to block quorum sensing (QS) could provide a route to attenuate virulence in bacterial pathogens. Considerable research has focused on this approach in Pseudomonas aeruginosa, which uses the LuxR-type receptor LasR to regulate much of its QS network. Non-native ligands that antagonize LasR have bee...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.06.007
更新日期：2018-09-20 00:00:00
abstract：:USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2017.03.002
更新日期：2017-04-20 00:00:00
abstract：:Small-molecule targeted recruitment of nucleases to RNA is a powerful method to affect RNA biology. Inforna, a sequence-based design approach to target RNA, enables the design of small molecules that bind to and cleave RNA in a selective and substoichiometric manner. Here, we investigate the ability of RNA-targeted de...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.04.008
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abstract：:This month: Lysosomal iron linked to cell death in cancer stem cells, non-enzymatic catalyst SynCAc for histone acylation, cytotoxins ivermectin and etoposide bring new anti-fungals out of the crypt, and 2'-deoxy-ADPR as second messenger activating TRPM2. ...
journal_title：Cell chemical biology
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doi：10.1016/j.chembiol.2017.07.016
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journal_title：Cell chemical biology
pub_type： 杂志文章
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abstract：:The translation of functionally active natural products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted ...
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journal_title：Cell chemical biology
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abstract：:This Perspective delineates how redox signaling affects the activity of specific enzyme isoforms and how this property may be harnessed for rational drug design. Covalent drugs have resurged in recent years and several reports have extolled the general virtues of developing irreversible inhibitors. Indeed, many modern...
journal_title：Cell chemical biology
pub_type： 杂志文章,评审
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abstract：:Owing to their structural flexibility, most serpins inhibit the cognate proteases in a fast and specific manner and also are susceptible to pathogenic misfolding. In this issue of Cell Chemical Biology, Madsen et al. (2016) report on the selection and characterization of an RNA aptamer that stabilizes α1-antichymotryp...
journal_title：Cell chemical biology
pub_type： 评论,杂志文章
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abstract：:Alport syndrome is a hereditary glomerular disease caused by mutation in type IV collagen α3-α5 chains (α3-α5(IV)), which disrupts trimerization, leading to glomerular basement membrane degeneration. Correcting the trimerization of α3/α4/α5 chain is a feasible therapeutic approach, but is hindered by lack of informati...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2018.02.003
更新日期：2018-05-17 00:00:00
abstract：:A protein-fragment complementation assay (PCA) for detecting and localizing intracellular protein-protein interactions (PPIs) was built by bisection of miniSOG, a fluorescent flavoprotein derived from the light, oxygen, voltage (LOV)-2 domain of Arabidopsis phototropin. When brought together by interacting proteins, t...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.07.007
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abstract：:Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime-containing small molecule caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferrop...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.09.014
更新日期：2019-12-19 00:00:00
abstract：:Because small-molecule activators of adenylyl cyclases (AC) affect ACs cell-wide, it is challenging to explore the signaling consequences of AC activity emanating from specific intracellular compartments. We explored this issue using a series of engineered, optogenetic, spatially restricted, photoactivable adenylyl cy...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.07.004
更新日期：2019-10-17 00:00:00
abstract：:H2S-producing enzymes in bacteria have been shown to be closely engaged in the process of microbial survival and antibiotic resistance. However, no inhibitors have been discovered for these enzymes, e.g., 3-mercaptopyruvate sulfurtransferase (MST). In the present study, we identified several classes of inhibitors for ...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2020.10.012
更新日期：2020-12-17 00:00:00
abstract：:Disorders of bone healing and remodeling are indications with an unmet need for effective pharmacological modulators. We used a high-throughput screen to identify activators of the bone marker alkaline phosphatase (ALP), and discovered 6,8-dimethyl-3-(4-phenyl-1H-imidazol-5-yl)quinolin-2(1H)-one (DIPQUO). DIPQUO marke...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2019.03.009
更新日期：2019-07-18 00:00:00
abstract：:Electron microscopy (EM) remains the primary method for imaging cellular and tissue ultrastructure, although simultaneous localization of multiple specific molecules continues to be a challenge for EM. We present a method for obtaining multicolor EM views of multiple subcellular components. The method uses sequential,...
journal_title：Cell chemical biology
pub_type： 杂志文章
doi：10.1016/j.chembiol.2016.10.006
更新日期：2016-11-17 00:00:00
