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Activity-based protein profiling for mapping and pharmacologically interrogating proteome-wide ligandable hotspots

Allison M Roberts, Carl C Ward, Daniel K Nomura
2017 Current Opinion in Biotechnology  
Here, we discuss modern methods for activitybased protein profiling-based chemoproteomic strategies to map 'ligandable' hotspots in proteomes using activity and reactivity-based chemical probes to allow  ...  Despite the completion of human genome sequencing efforts nearly 15 years ago that brought with it the promise of genomebased discoveries that would cure human diseases, most protein targets that control  ...  Acknowledgements We thank the members of the Nomura Research Group for critical reading of the manuscript.  ... 
doi:10.1016/j.copbio.2016.08.003 pmid:27568596 pmcid:PMC5305418 fatcat:zl6riwnrinc2zbujhsjjz2mr6u

Target Identification of Bioactive Covalently Acting Natural Products [chapter]

Daniel K. Nomura, Thomas J. Maimone
2018 Current Topics in Microbiology and Immunology  
chemical probes to profile proteome-wide reactive, functional, and ligandable hotspots directly in complex proteomes (Fig. 5b, c) .  ...  probes to profile proteome-wide reactive and ligandable hotspots in complex proteomes.  ... 
doi:10.1007/82_2018_121 pmid:30105423 fatcat:7qxfb5snvzfrbawauylxlb6ekm

Druggable Targets and Targeted Drugs: Enhancing the Development of New Therapeutics

Melvin L. Billingsley
2008 Pharmacology  
The convergence of novel druggable targets with new chemical entities that can be specifically targeted to disease-causing sites and genes represents one means of creating highly efficacious and specific  ...  In spite of these advances, the gross measure of approvable drug output is declining, with only 17 new chemical entities approved by the FDA in 2007.  ...  Small molecule chemical libraries are often coupled with high-throughput screening of defined protein targets to profile 'chemical space'; this approach has led to the identification of lead compounds  ... 
doi:10.1159/000157624 pmid:18802381 fatcat:dnenvnh3qnclfmawgarweqz2gm

Multiscale Modelling of Relationships between Protein Classes and Drug Behavior Across all Diseases Using the CANDO Platform

Geetika Sethi, Gaurav Chopra, Ram Samudrala
2015 Mini-Reviews in Medical Chemistry  
The first version of the CANDO platform utilizes a matrix of predicted interactions between 48278 proteins and 3733 human ingestible compounds (including FDA approved drugs and supplements) that map to  ...  Keywords Druggable proteins; protein drug interactions; protein folds; protein classes; proteome drug discovery; drug discovery benchmark; multiscale modeling; polypharmacology Sethi et al.  ...  The study was supported by a NIH Director's Pioneer Award (1DP1OD006779-01) to Ram Samudrala and a JDRF fellowship to Gaurav Chopra.  ... 
doi:10.2174/1389557515666150219145148 pmid:25694071 pmcid:PMC5903852 fatcat:lt2qtjtq7fhdplgt7jttmow5rm

A practical view of 'druggability'

Thomas H Keller, Arkadius Pichota, Zheng Yin
2006 Current Opinion in Chemical Biology  
This is best explained using the cartoon representation of chemical space introduced by Lipinski and Hopkins (Figure 1 ) [23 ] where compounds are mapped onto coordinates of chemical descriptors of  ...  A close-up of the cartoon in Figure 1 that shows the chemical space occupied by active site serine protease inhibitors.  ...  Interestingly, the impact of druggability on these attrition rates is not discussed. 2. Lipinski CA: Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov Today:  ... 
doi:10.1016/j.cbpa.2006.06.014 pmid:16814592 fatcat:e3cq6546vjdjroqxafx5wjnt6e

The Mycobacterium tuberculosis Drugome and Its Polypharmacological Implications

Sarah L. Kinnings, Li Xie, Kingston H. Fung, Richard M. Jackson, Lei Xie, Philip E. Bourne, Ruth Nussinov
2010 PLoS Computational Biology  
The TB-drugome reveals that approximately one-third of the drugs examined have the potential to be repositioned to treat tuberculosis and that many currently unexploited M.tb receptors may be chemically  ...  druggable and could serve as novel anti-tubercular targets.  ...  Acknowledgments We appreciate the constructive suggestions of the anonymous reviewers and the editor in improving the manuscript. We thank Dr.  ... 
doi:10.1371/journal.pcbi.1000976 pmid:21079673 pmcid:PMC2973814 fatcat:434vr2sbgjhfzk5qfub7m3aofi

Biomolecular NMR: a chaperone to drug discovery

M BETZ, K SAXENA, H SCHWALBE
2006 Current Opinion in Chemical Biology  
Biomolecular NMR now contributes routinely to every step in the development of new chemical entities ahead of clinical trials.  ...  The versatility of NMR--from detection of ligand binding over a wide range of affinities and a wide range of drug targets with its wealth of molecular information, to metabolomic profiling, both ex vivo  ...  Acknowledgement Work supported by the Center for Biomolecular Magnetic Resonance through a grant of the state of Hesse.  ... 
doi:10.1016/j.cbpa.2006.04.006 pmid:16679046 pmcid:PMC7185745 fatcat:tnl33hakmjaunn6nm65o6y7wfu

Predicting Selectivity and Druggability in Drug Discovery [chapter]

Alan C. Cheng
2008 Annual Reports in Computational Chemistry  
Some have pointed out that the much larger "druggable proteome" or "druggable targetome" is more relevant than the "druggable genome" [67] .  ...  In the original SARAH idea, experimentally measured affinities for a diverse set of compounds represent an "affinity fingerprint" for a target, and similar pharmacological profiles would indicate target  ... 
doi:10.1016/s1574-1400(08)00002-9 fatcat:23tyvzeezrfy5pmom3tooj7yta

Bioinformatics in translational drug discovery

Sarah K. Wooller, Graeme Benstead-Hume, Xiangrong Chen, Yusuf Ali, Frances M.G. Pearl
2017 Bioscience Reports  
Competing interests The authors declare that there are no competing interests associated with the manuscript.  ...  ; GWAS, genome-wide association studies; HCV, hepatitis C virus; HR, homologous recombination; PSA, polar surface area; SSBR, single-strand break repair; SSL, synthetically sensitive or lethal; TCGA, The  ...  Alternatively, it is possible to map the gene expression profile that is associated with disease and compare it with pre-existing profiles that are associated with drugs [65] .  ... 
doi:10.1042/bsr20160180 pmid:28487472 fatcat:iffd7elku5b5fbnrggvpwzbqn4

Hydrazines as versatile chemical biology probes and drug-discovery tools for cofactor-dependent enzymes [article]

Zongtao Lin, Xie Wang, Katelyn A Bustin, Lin He, Radu M Suciu, Nancy Schek, Mina Ahmadi, Kai Hu, Erika J Olson, Will H Parsons, Eric S Witze, Paul D Morton (+3 others)
2020 biorxiv/medrxiv   pre-print
Here, we have innovated a versatile class of chemoproteomic probes for this less charted hemisphere of the proteome by using hydrazine as the common chemical warhead.  ...  The capacity of substituted hydrazines to profile, discover and inhibit diverse cofactor-dependent enzymes enables cell and tissue imaging and makes this platform useful for enzyme and drug discovery.  ...  It should be possible to further elaborate probe molecules to develop more selective compounds that enable spatially resolved activity maps for existing histological samples and chemical druggability maps  ... 
doi:10.1101/2020.06.17.154864 fatcat:7ukltv6u4zagtpzy2t62ikt4gq

Multi-Omics Technologies Applied to Tuberculosis Drug Discovery

Aaron Goff, Daire Cantillon, Leticia Muraro Wildner, Simon J Waddell
2020 Applied Sciences  
Firstly, in a discovery biology approach, to find new targets in druggable pathways for target-based investigation, advancing from target to lead compound.  ...  This review summarizes the application of Mycobacterium tuberculosis omics technologies to the early stages of tuberculosis antimicrobial drug discovery.  ...  MmpL3 is an integral inner membrane transporter, with a role in the export of mycolic acids to the periplasmic space in the biosynthesis of the mycobacterial cell wall.  ... 
doi:10.3390/app10134629 fatcat:nz63bhm635fkbmbokv3aux7pqa

Interrogating the druggable genome with structural informatics

Kevin Hambly, Joseph Danzer, Steven Muskal, Derek A. Debe
2006 Molecular diversity  
We report here a detailed analysis of the structural coverage for the set of druggable human targets, highlighting drug target families where the level of structural knowledge is currently quite high,  ...  In this paper, we present the Target Informatics Platform (TIP), a novel structural informatics approach for amplifying the rapidly expanding body of experimental protein structure information to enhance  ...  Structural coverage for druggable target space To define the space of known and potential druggable targets in the human genome, we used a sequence-domain based approach for annotation and retrieval of  ... 
doi:10.1007/s11030-006-9035-3 pmid:17031532 fatcat:xjdq6lzlh5ht3jsnuxen4eqqrq

canSAR: an integrated cancer public translational research and drug discovery resource

Mark D. Halling-Brown, Krishna C. Bulusu, Mishal Patel, Joe E. Tym, Bissan Al-Lazikani
2011 Nucleic Acids Research  
canSAR is a fully integrated cancer research and drug discovery resource developed to utilize the growing publicly available biological annotation, chemical screening, RNA interference screening, expression  ...  This allows easy access to the multidisciplinary data within, including target and compound synopses, bioactivity views and expert tools for chemogenomic, expression and protein interaction network data  ...  ACKNOWLEDGEMENTS The authors acknowledge data providers (ChEMBL, BindingDB, ArrayExpress,  ... 
doi:10.1093/nar/gkr881 pmid:22013161 pmcid:PMC3245005 fatcat:xdiuj2msgnep5hltiov6qp3qoe

Development of a chemogenomics library for phenotypic screening

Bryan Dafniet, Natacha Cerisier, Batiste Boezio, Anaelle Clary, Pierre Ducrot, Thierry Dorval, Arnaud Gohier, David Brown, Karine Audouze, Olivier Taboureau
2021 Journal of Cheminformatics  
However, phenotypic screening does not rely on knowledge of specific drug targets and needs to be combined with chemical biology approaches to identify therapeutic targets and mechanisms of actions induced  ...  phenotypic profiling assay known as "Cell Painting".  ...  Acknowledgements We would like to thank the doctoral school "Pierre Louis de santé publique" and the pharmaceutical company Servier for their support on this study.  ... 
doi:10.1186/s13321-021-00569-1 pmid:34819133 pmcid:PMC8611952 fatcat:k5ze5hfad5ehtokoq7qguzkzoa

Visualizing the drug target landscape

Stephen J. Campbell, Anna Gaulton, Jason Marshall, Dmitri Bichko, Sid Martin, Cory Brouwer, Lee Harland
2010 Drug Discovery Today  
A retrospective on how the application of data integration and visualisation has been used to connect disparate information sources into a drug-discovery focused, decision making environment.  ...  Acknowledgements The authors acknowledge the guidance of Enoch Huang and substantial input from Robert Hernandez, Markella Skempri, Dave  ...  This can be achieved using the filter mechanism to display the scores calculated for any data component as a heat map across the proteome.  ... 
doi:10.1016/j.drudis.2009.09.011 pmid:19840866 fatcat:csd4hsaokjgbjjbq4azwdnf24q
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