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Computational-experimental approach to drug-target interaction mapping: A case study on kinase inhibitors

Anna Cichonska, Balaguru Ravikumar, Elina Parri, Sanna Timonen, Tapio Pahikkala, Antti Airola, Krister Wennerberg, Juho Rousu, Tero Aittokallio, Avner Schlessinger
2017 PLoS Computational Biology  
As a specific case study, we used tivozanib, an investigational VEGF receptor inhibitor with currently unknown off-target profile.  ...  To evaluate its performance, we first predicted unmeasured binding affinities in a large-scale kinase inhibitor profiling study, and then experimentally tested 100 compound-kinase pairs.  ...  Acknowledgments The authors would like to thank Dr. Lari Lehtiö for careful reading and expert comments on the manuscript, Dr.  ... 
doi:10.1371/journal.pcbi.1005678 pmid:28787438 pmcid:PMC5560747 fatcat:yfmm5krapveczelik4nz2b67fe

On the Origins of Enzyme Inhibitor Selectivity and Promiscuity: A Case Study of Protein Kinase Binding to Staurosporine

Duangrudee Tanramluk, Adrian Schreyer, William R. Pitt, Tom L. Blundell
2009 Chemical Biology and Drug Design  
I have developed a statistical approach based on the Mantel test to find the relationship between the shapes of ATP binding sites and their affinities for inhibitors. My shape-based dendrogram shows  ...  ABSTRACT Protein kinases are important regulatory enzymes in signal transduction and in cell regulation.  ...  Pitt WR, Blundell TL (2009) On the Origins of Enzyme Inhibitor Selectivity and Promiscuity: A Case Study of Protein Kinase Binding to Staurosporine.  ... 
doi:10.1111/j.1747-0285.2009.00832.x pmid:19519740 pmcid:PMC2737611 fatcat:crnexul2tzcvvg236diu2mrcbm

Mapping genetic interactions in cancer: a road to rational combination therapies

Beril Tutuncuoglu, Nevan J. Krogan
2019 Genome Medicine  
We further focus on factors that should be considered in order to develop a robust analysis pipeline.  ...  The development of targeted therapeutic agents is premised on mapping the physical and functional dependencies of mutated genes in cancer.  ...  Acknowledgements We would like to thank Manon Eckhardt and Minkyu Kim for critical reading of the manuscript. We would also like to thank Mike Shales for assistance with graphics.  ... 
doi:10.1186/s13073-019-0680-4 pmid:31640753 pmcid:PMC6805649 fatcat:lf7kz7mpnrfg5bt5cax7b4atbi

Systematic Mapping of Kinase Addiction Combinations in Breast Cancer Cells by Integrating Drug Sensitivity and Selectivity Profiles

Agnieszka Szwajda, Prson Gautam, Leena Karhinen, Sawan Kumar Jha, Jani Saarela, Sushil Shakyawar, Laura Turunen, Bhagwan Yadav, Jing Tang, Krister Wennerberg, Tero Aittokallio
2015 Chemistry and Biology  
Graphical Abstract Highlights d Chemical systems biology tool for mapping kinase signal addictions in cancer cells d Makes use of a network of interactions between kinase inhibitors and their targets d  ...  In this study, we developed a chemical systems biology approach that integrates comprehensive drug sensitivity and selectivity profiling to provide functional insights into both single and multi-target  ...  Carina von Schantz-Fant, Katja Suomi, and Elina Huovari from the High Throughput Biology Unit at FIMM, as well as Arjan van Adrichem for their great technical assistance and help in performing the drug  ... 
doi:10.1016/j.chembiol.2015.06.021 pmid:26211361 fatcat:cpbcjdd47fgfjnmqlvvecq4kca

Computational Insights for the Discovery of Non-ATP Competitive Inhibitors of MAP Kinases

Michael J. Schnieders, Tamer S. Kaoud, Chunli Yan, Kevin N. Dalby, Pengyu Ren
2012 Current pharmaceutical design  
Special emphasis is placed on the role of computational methods in the drug discovery process for MAP kinases.  ...  Due to their role in cellular signaling mitogen activated protein (MAP) kinases represent targets of pharmaceutical interest.  ...  Support from Texas Institute for Drug & Diagnostic Development H-F-0032 is also acknowledged by K. N. Dalby. T.S.K. acknowledges a scholarship from the Egyptian Ministry of Higher Education.  ... 
doi:10.2174/138161212799436368 pmid:22316156 pmcid:PMC4016787 fatcat:d4646anrzzak3lbuujppavmowa

The Biochemistry, Biology and Pathology of MAP Kinases II, 10-11 September 2014, Vilnius - Lithuania

Jonas Cicenas, Rony Seger, Jean-François Bodart, Mindaugas Valius
2014 MAP Kinase  
A SYSTEMS BIOMEDICINE APPROACH TOWARDS MODELLING THE MAP KINASE PATHWAYS Karthik Kalyan Haffkine Institute, Mumbai, India and MAP Kinase Resource, Bern, Switzerland Systems Biology is the study of interactions  ...  Computational approaches such as Differential Equation based (DEB) approaches can be used model the role of MAP Kinase signaling pathways at various spatial and temporal scales.  ... 
doi:10.4081/mk.2014.4812 fatcat:36hgauxprvfn5p5q5pvtboeexe

Crowdsourced mapping of unexplored target space of kinase inhibitors

Anna Cichońska, Balaguru Ravikumar, Robert J. Allaway, Fangping Wan, Sungjoon Park, Olexandr Isayev, Shuya Li, Michael Mason, Andrew Lamb, Ziaurrehman Tanoli, Minji Jeon, Sunkyu Kim (+95 others)
2021 Nature Communications  
Effective approaches are therefore required to map the massive space of unexplored compound–kinase interactions for novel and potent activities.  ...  We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts.  ...  Acknowledgements The authors thank the IDG Kinase Data and Resource Generation Center for generating new sets of target activity data for the Challenge Rounds 1 and 2, Olle Hansson (FIMM) for technical  ... 
doi:10.1038/s41467-021-23165-1 pmid:34083538 fatcat:otj4dir66bhahci4fj56ifbw5a

Protein flexibility in docking and surface mapping

Katrina W. Lexa, Heather A. Carlson
2012 Quarterly Reviews of Biophysics (print)  
Typical protein-ligand docking efforts still rely on a single rigid receptor, which is an incomplete representation of potential binding conformations of the protein.  ...  Structure-based drug design has become an essential tool for rapid lead discovery and optimization.  ...  Computational solvent mapping is a complementary approach to experimental fragment-binding studies; however, most computational approaches do not account for either the impact of protein flexibility or  ... 
doi:10.1017/s0033583512000066 pmid:22569329 pmcid:PMC4272345 fatcat:s7voxcdb7zbyrgkt7kedvo3lky

Predicting a small molecule-kinase interaction map: A machine learning approach

Fabian Buchwald, Lothar Richter, Stefan Kramer
2011 Journal of Cheminformatics  
We present a machine learning approach to the problem of protein ligand interaction prediction. We focus on a set of binding data obtained from 113 different protein kinases and 20 inhibitors.  ...  Results: A Support Vector Machine (SVM) as well as a decision tree algorithm (C5/See5) is used to learn models based on the available features which in turn can be used for the classification of new kinase-inhibitor  ...  FB, LR and SK made substantial contributions to the conception, design and coordination of the study.  ... 
doi:10.1186/1758-2946-3-22 pmid:21708012 pmcid:PMC3151211 fatcat:m6oooenjj5amplx44ilaor3ryu

JNK inhibitors: is there a future?

Jonas Cicenas
2015 MAP Kinase  
JNK is a subfamily of MAP kinases that hat regulates a range of biological processes implicated in response to stress, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock as well  ...  The realization of the therapeutic potential of the inhibition of JNKs led to a thorough search for small-molecule inhibitors first for research purposes, but later also for therapeutic applications.  ...  On the other hand, new approached, such like computer-assisted, 3D structure based approaches to generate new generations of kinase inhibitors 112 might solve a lot of problems as well.  ... 
doi:10.4081/mk.2015.5700 fatcat:ayad7oiycfgqdk3jmrxozteeui

A human MAP kinase interactome

Sourav Bandyopadhyay, Chih-yuan Chiang, Jyoti Srivastava, Merril Gersten, Suhaila White, Russell Bell, Cornelia Kurschner, Christopher H Martin, Mike Smoot, Sudhir Sahasrabudhe, Diane L Barber, Sumit K Chanda (+1 others)
2010 Nature Methods  
Toward this goal, we pursued a combined experimental and computational approach to assemble a large resource of MAPK protein interactions and to illustrate methods to functionally explore such a network  ...  and computational approach to map 2,269 interactions between human maPK-related proteins and other cellular machinery and to assemble these data into functional modules. multiple lines of evidence including  ...  It has been postulated that up to one-third of MAP-family kinases are associated with the microtubule cytoskeleton 7 .  ... 
doi:10.1038/nmeth.1506 pmid:20936779 pmcid:PMC2967489 fatcat:jsseza3ul5gb3frtqyksdiinc4

Systematic mapping of cancer cell target dependencies using high-throughput drug screening in triple-negative breast cancer

Tianduanyi Wang, Prson Gautam, Juho Rousu, Tero Aittokallio
2020 Computational and Structural Biotechnology Journal  
To that end, we developed a computational target deconvolution pipeline that identifies the key target dependencies based on collective drug response patterns in each cell line separately.  ...  Our integrated approach also recovered a number of well-established TNBC cell line-specific drivers and known TNBC therapeutic targets, such as HDACs and cyclin-dependent kinases (CDKs).  ...  Therefore, kinase inhibitors in particular require multi-target deconvolution approaches.  ... 
doi:10.1016/j.csbj.2020.11.001 pmid:33335681 pmcid:PMC7720026 fatcat:dka2gcbdvbfgxn3euafawok3r4

Systems biology analysis of G protein and MAP kinase signaling in yeast

N Hao, M Behar, T C Elston, H G Dohlman
2007 Oncogene  
Moreover, today's molecular pharmacologists are accustomed to working on narrowly focused problems centered on a single protein or enzymatic process.  ...  However, the complexity of G protein signaling mechanisms has significantly hampered our ability to identify additional new drug targets.  ...  One strategy is to use genetics to identify protein binding partners of a dysfunctional gene product, as any interacting proteins represent alternative (nonmutated) targets for drug therapy (Hartwell  ... 
doi:10.1038/sj.onc.1210416 pmid:17496920 fatcat:llzkvn5h7zcmjkwkvmtr5rbbve

Pharmacophore Mapping Approach for Drug Target Identification: A Chemical Synthesis and in Silico Study on Novel Thiadiazole Compounds

Rohan J. Meshram
2017 Journal of Clinical and Diagnostic Research  
To effectively synthesize di substituted thiadiazole compounds and demonstrate drug target identification using an in silico pharmacophore probing approach.  ...  Moreover, we also aim to validate the suitability of identified drug target.  ...  Only human protein target set was utilized for pharmacophore mapping in this study. Rest of parameters was set to default values.  ... 
doi:10.7860/jcdr/2017/22761.9925 pmid:28658808 pmcid:PMC5483710 fatcat:ro5tbt5q4jhy3chmmnkzfbk2dm

COMPUTATIONAL GENERATION INHIBITOR-BOUND CONFORMERS OF P38 MAP KINASE AND COMPARISON WITH EXPERIMENTS [chapter]

AHMET BAKAN, IVET BAHAR
2010 Biocomputing 2011  
A useful strategy in such complicated cases is to perform ensemble-docking provided that a representative set of conformers is available for the target protein either from computations or experiments.  ...  The p38 MAP kinases play a critical role in regulating stress-activated pathways, and serve as molecular targets for controlling inflammatory diseases.  ...  In a previous study, based on small sets of PDB structures for four different kinases, local changes in the glycine rich loop (a -hairpin that interacts with inhibitors) of the N-terminal lobe were observed  ... 
doi:10.1142/9789814335058_0020 fatcat:v6lvg42ccza35kjeglnkrn3csq
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