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Searching for the Holy Grail; protein–protein interaction analysis and modulation

Xavier Morelli, Ted Hupp
2012 EMBO Reports  
A fter more than a decade spent struggling to discover what features of a protein are 'druggable', the modulation of protein-protein interactions (PPIs) has emerged from both academic and corporate research  ...  The two topics we have chosen to highlight in this meeting report-PPIs in system biology and PPI modulation-were main focuses of the workshop. Xavier Morelli is a group leader at  ...  ACKNOWLEDGEMENTS The authors thank V. Ferrier and P. Colas for help and advice with the article and all the speakers who agreed to have their work cited here.  ... 
doi:10.1038/embor.2012.137 pmid:22986552 pmcid:PMC3463974 fatcat:eqxjl2urmbedtcjzbamzepcqma

Leaving no stone unturned: Allosteric targeting of SARS-CoV-2 Spike protein at putative druggable sites disrupts human angiotensin-converting enzyme interactions at the receptor binding domain

Fisayo A. Olotu, Kehinde F. Omolabi, Mahmoud E.S. Soliman
2020 Informatics in Medicine Unlocked  
Estimated ΔG binds for both compounds were highly favorable due to high-affinity interactions at the target sites.  ...  The systematic entry of SARS-CoV-2 into host cells, as mediated by its Spike (S) protein, is highly essential for pathogenicity in humans.  ...  Acknowledgement Authors thank the college of health sciences, University of KwaZulu-Natal, South Africa for providing infrastructural support and we also acknowledge the Center for High Performance Computing  ... 
doi:10.1016/j.imu.2020.100451 pmid:33083517 pmcid:PMC7561517 fatcat:dp3ht2tt2fce3o3334wkq2bksy

Systems Perturbation Analysis of a Large Scale Signal Transduction Model Reveals Potentially Influential Candidates for Cancer Therapeutics [article]

Bhanwar Lal Puniya, Laura Allen, Colleen Hochfelder, Mahbubul Majumder, Tomáš Helikar
2015 arXiv   pre-print
Based on the premise that the most influential components might serve as better drug targets, we characterized them for biological functions, housekeeping genes, essential genes, and druggable proteins  ...  Moreover, known cancer drug targets were also classified in influential components based on the affected components in the network.  ...  Often the specific causal interactions of the disease state are hidden within the massive cell-wide alterations, making attempts to reverse a disease state more challenging.  ... 
arXiv:1511.03337v1 fatcat:o577doj3rrbuzcpadx6qobp2ai

Druggable Transient Pockets in Protein Kinases

Koji Umezawa, Isao Kii
2021 Molecules  
Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention.  ...  Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY.  ...  Conflicts of Interest: The authors declare no conflict of interest.  ... 
doi:10.3390/molecules26030651 pmid:33513739 fatcat:vj4jixt5trgqhdjt2b2jdlkjhm

Bioinformatics and variability in drug response: a protein structural perspective

J. L. Lahti, G. W. Tang, E. Capriotti, T. Liu, R. B. Altman
2012 Journal of the Royal Society Interface  
In this review, we first summarize structural characteristics of protein targets and common mechanisms of drug interactions.  ...  Over the past decade, progress in structural genomics led to an explosion of available three-dimensional structures of drug target proteins while efforts in pharmacogenetics offered insights into polymorphisms  ...  Instead, three-dimensional structures can provide information more relevant to protein druggability. In a seminal paper, Cheng et al.  ... 
doi:10.1098/rsif.2011.0843 pmid:22552919 pmcid:PMC3367825 fatcat:olvu5dx4rnaahpeadr6yhntwau

Protein-Protein Interactions: Structures and Druggability [chapter]

David B. Ascher, Harry C. Jubb, Douglas E. V. Pires, Takashi Ochi, Alicia Higueruelo, Tom L. Blundell
2015 Multifaceted Roles of Crystallography in Modern Drug Discovery  
While protein-protein interfaces have promised a range of benefits over conventional sites in drug discovery, they present unique challenges.  ...  Here we describe recent developments that facilitate many aspects of the drug discovery process -including characterization and classification of interfaces, identifying druggable sites and strategies  ...  Protein-Protein Interactions: Structures and Druggability Protein-Protein Interactions: Structures and Druggability Protein-Protein Interactions: Structures and Druggability Protein-Protein  ... 
doi:10.1007/978-94-017-9719-1_12 fatcat:2bn2nkxs7fflzia2lvqt7osccq

Prediction of Druggable Proteins Using Machine Learning and Systems Biology: A Mini-Review

Gaurav Kandoi, Marcio L. Acencio, Ney Lemke
2015 Frontiers in Physiology  
In this mini-review, we describe promising approaches based on the simultaneous use of systems biology and machine learning to access gene and protein druggability.  ...  In recent years the scientific community has explored the combined power of these fields to propose increasingly accurate and low cost methods to propose interesting drug targets.  ...  MLA has been supported by the Coordination for the Improvement of Higher Education Personnel (CAPES) in Brazil.  ... 
doi:10.3389/fphys.2015.00366 pmid:26696900 pmcid:PMC4672042 fatcat:rvenukj5pzca5irvgbpu4xt4ha

Druggability of methyl-lysine binding sites

C. Santiago, K. Nguyen, M. Schapira
2011 Journal of Computer-Aided Molecular Design  
We show that these target classes are generally less druggable than bromodomains, but that some proteins stand as notable exceptions.  ...  We find that limited protein backbone motion or the presence of side-cavities juxtaposed to the methyl-lysine binding pocket can significantly improve druggability.  ...  ) results in a significant variation in predicted druggability: the methyl group of T411 produces a more enclosed and more hydrophobic pocket, two features that increase its Dscore.  ... 
doi:10.1007/s10822-011-9505-2 pmid:22146969 fatcat:vxhu5tyt4rfpjocolrdfgfetbm

Expanding the Druggable Space of the LSD1/CoREST Epigenetic Target: New Potential Binding Regions for Drug-Like Molecules, Peptides, Protein Partners, and Chromatin

James C. Robertson, Nate C. Hurley, Marcello Tortorici, Giuseppe Ciossani, Maria Teresa Borrello, Nadeem A. Vellore, A. Ganesan, Andrea Mattevi, Riccardo Baron, James M. Briggs
2013 PLoS Computational Biology  
in protein interactions.  ...  Lysine specific demethylase-1 (LSD1/KDM1A) in complex with its corepressor protein CoREST is a promising target for epigenetic drugs.  ...  Acknowledgments The authors thank the Center for High Performance Computing for technical support and computing allocations, and Tanggis Bohnuud from Prof.  ... 
doi:10.1371/journal.pcbi.1003158 pmid:23874194 pmcid:PMC3715402 fatcat:6q4qfvcc4rerljcwoyskigb5mi

Druggability Assessment of Allosteric Proteins by Dynamics Simulations in the Presence of Probe Molecules

Ahmet Bakan, Neysa Nevins, Ami S. Lakdawala, Ivet Bahar
2012 Journal of Chemical Theory and Computation  
Druggability assessment of a target protein has emerged in recent years as an important concept in hit-to-lead optimization.  ...  A reliable and physically relevant measure of druggability would allow informed decisions on the risk of investing in a particular target.  ...  Intrinsic Dynamics of the Target Protein and the Effect of Probe Molecules.  ... 
doi:10.1021/ct300117j pmid:22798729 pmcid:PMC3392909 fatcat:k5n4bw7vcfbnnn5owawgxjxiyq

Identifying Drug Targets in Pancreatic Ductal Adenocarcinoma Through Machine Learning, Analyzing Biomolecular Networks, and Structural Modeling

Wenying Yan, Xingyi Liu, Yibo Wang, Shuqing Han, Fan Wang, Xin Liu, Fei Xiao, Guang Hu
2020 Frontiers in Pharmacology  
The protein-drug interactions and hinge sites predication of ITGAV and ITGA2 suggest potential drug binding residues in the Thigh domain.  ...  Herein, we developed a computational method of predicting cancer genes and anticancer drug targets that combined three independent expression microarray datasets of PDAC patients and protein-protein interaction  ...  In particular, the non-drug target ITGA2 had a larger DS than ITGAV, suggesting that a more detailed structural comparison between these two integrin proteins is needed.  ... 
doi:10.3389/fphar.2020.00534 pmid:32425783 pmcid:PMC7204992 fatcat:fxmiwl7ehjervf4kbsnnr7rwce

Modulating Protein-Protein Interactions: From Structural Determinants of Binding to Druggability Prediction to Application

Alexander Metz, Emanuele Ciglia, Holger Gohlke
2012 Current pharmaceutical design  
In the second section, we present how some of the characteristics of protein-protein interactions can be exploited fruitfully in drug design, hence focusing on the druggability of protein-protein interfaces  ...  During the last decades, a large amount of evidence has been gathered on the importance of protein-protein interactions in tuning and regulating most important biological processes.  ...  ACKNOWLEDGEMENTS We acknowledge a fruitful collaboration with the group of Manuel Grez at Georg-Speyer-Haus, Frankfurt, on modulating NHR2 tetramerization. We also thank D. Grimme and D.  ... 
doi:10.2174/138161212802651553 pmid:22650257 fatcat:3jfjdajiz5hkbjcng6pm3osaym

Binding cavities and druggability of intrinsically disordered proteins

Yugang Zhang, Huaiqing Cao, Zhirong Liu
2015 Protein Science  
The geometries of the cavities of IDPs differ from the cavities of ordered proteins, for example, the cavities of IDPs have larger surface areas and volumes, and are more likely to be composed of a single  ...  The druggability of the cavities was examined, and the average druggable probability is estimated to be 9% for IDPs, which is almost twice that for ordered proteins (5%).  ...  Acknowledgments The authors thank Prof. Luhua Lai, Dr. Yongqi Huang, and Chen Yu for helpful discussions.  ... 
doi:10.1002/pro.2641 pmid:25611056 pmcid:PMC4420519 fatcat:zfnzhv3wnrgipkswgr62lsvsga

Systems Pharmacology: An Overview [chapter]

Marc R. Birtwistle, Jens Hansen, James M. Gallo, Sreeharish Muppirisetty, Peter Man-Un Ung, Ravi Iyengar, Avner Schlessinger
2016 Systems Pharmacology and Pharmacodynamics  
Networks of protein-protein interactions that were confirmed by experimental and computational analysis of the structure of the interaction partners can be combined with graph theory to identify modules  ...  Systems pharmacology has evolved from a discipline that focuses on drug action at the organ level to a discipline that combines traditional pharmacokinetic and pharmacodynamic modeling with recent systems  ...  For instance, a highly connected node in a protein-protein interaction (PPI) network can be a protein that interacts with multiple partners through the same surface region at different times in different  ... 
doi:10.1007/978-3-319-44534-2_4 fatcat:hnkzgvppa5ehjcqj65vw43fily

Screening of druggable conformers of α-synuclein using molecular dynamics simulation

2020 Biointerface Research in Applied Chemistry  
IDPs structural binding pockets and their flexibility exist as a challenging target for standard druggable approaches.  ...  Hence, in this study, we have performed and identified the most probable druggable conformers from molecular dynamics simulation on α-synuclein based on the structural parameters: radius of gyration (Rg  ...  Allowing their highly dynamic nature into consideration, we have performed Molecular dynamics simulation on αsynuclein protein, a typical IDP, to get a better sampling of conformers.  ... 
doi:10.33263/briac103.338347 fatcat:wwn2omuxyneqxkt76fbqtmya64
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