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A Virtual Screen Discovers Novel, Fragment-Sized Inhibitors of Mycobacterium tuberculosis InhA

Alexander L. Perryman, Weixuan Yu, Xin Wang, Sean Ekins, Stefano Forli, Shao-Gang Li, Joel S. Freundlich, Peter J. Tonge, Arthur J. Olson
2015 Journal of Chemical Information and Modeling  
The best two inhibitors discovered are both fragment-sized compounds and displayed K i values of 54 and 59 μM, respectively.  ...  Importantly, the novel inhibitors discovered have low structural similarity to known InhA inhibitors and, thus, help expand the number of chemotypes on which future medicinal chemistry efforts can be focused  ...  We thank Sargis Dallakyan for maintaining the server that was used to submit these virtual screens to the GO FAM project and to receive the results from it.  ... 
doi:10.1021/ci500672v pmid:25636146 pmcid:PMC4386068 fatcat:msoyu5a5cbawzokf33xjc7nhmm

InhA inhibitors as potential antitubercular agents

Hinna Hamid
2016 Oriental Journal of Chemistry  
Tuberculosis (TB) is a potentially serious infectious disease.  ...  Isoniazid (INH), the first-line agent used for prevention and treatment of tuberculosis targets the enoyl reductase (InhA) enzyme in fatty acid biosynthesis pathway of the mycobacteria.  ...  The two best inhibitors that were discovered showed K i values of 54 and 59 mM, respectively and were fragment-sized analogues ( fig.6 ).Novel inhibitors discovered in this study had very little similarity  ... 
doi:10.13005/ojc/320106 fatcat:ohzseqvcmrdufl7zrdpwfhruoa

Identification of potential inhibitor targeting enoyl-acyl carrier protein reductase (InhA) in Mycobacterium tuberculosis: a computational approach

V. Shanthi, K. Ramanathan
2013 3 Biotech  
The explosive global spreading of multidrug resistant Mycobacterium tuberculosis (Mtb) has provoked an urgent need to discover novel anti-TB agents.  ...  We believe that this novel scaffolds might be the good starting point for lead compounds and certainly aid the experimental designing of anti-tuberculosis drug in a short time.  ...  Conflict of interest The authors declare that they have no conflict of interest.  ... 
doi:10.1007/s13205-013-0146-0 pmid:28324429 pmcid:PMC4026456 fatcat:j47mxaxvxjdgri5j47op6vibeu

New Approaches to Target the Mycolic Acid Biosynthesis Pathway for the Development of Tuberculosis Therapeutics

E. North, Mary Jackson, Richard Lee
2013 Current pharmaceutical design  
In this review, we analyze the new and emerging inhibitors of this pathway discovered in the post-genomic era of tuberculosis drug discovery, several of which show great promise as selective tuberculosis  ...  The large size of these unique fatty acids is a result of a huge metabolic investment that has been evolutionarily conserved, indicating the importance of these lipids to the mycobacterial cellular survival  ...  Acknowledgments The authors' research on mycolic acid inhibitors is supported through the National Institutes of Health grants AI062415 and AI063054 and the American Lebanese Syrian Associated Charities  ... 
doi:10.2174/1381612819666131118203641 pmid:24245756 pmcid:PMC4568743 fatcat:ajmiyvpywvgerdwtj7wllkat4q

Drug Discovery Using Chemical Systems Biology: Repositioning the Safe Medicine Comtan to Treat Multi-Drug and Extensively Drug Resistant Tuberculosis

Sarah L. Kinnings, Nina Liu, Nancy Buchmeier, Peter J. Tonge, Lei Xie, Philip E. Bourne, James M. Briggs
2009 PLoS Computational Biology  
More generally, the protocol described in this paper can be included in a drug discovery pipeline in an effort to discover novel drug leads with desired safety profiles, and therefore accelerate the development  ...  The minimal inhibition concentration (MIC 99 ) of entacapone for Mycobacterium tuberculosis (M.tuberculosis) is approximately 260.0 mM, well below the toxicity concentration determined by an in vitro cytotoxicity  ...  Introduction Tuberculosis, which is caused by the bacterial pathogen Mycobacterium tuberculosis (M.tuberculosis), is a leading cause of mortality among infectious diseases.  ... 
doi:10.1371/journal.pcbi.1000423 pmid:19578428 pmcid:PMC2699117 fatcat:etbdthw3yjcxbpzmbdzbm6gvq4

Computational Deorphaning of Mycobacterium tuberculosis Targets [chapter]

Lorraine Yamurai Bishi, Dr Sundeep Chaitanya Vedithi, Tom L. Blundell, Grace Mugumbate
2019 Tuberculosis - Beyond the Biomedical [Working Title]  
Tuberculosis (TB) continues to be a major health hazard worldwide due to the resurgence of drug discovery strains of Mycobacterium tuberculosis (Mtb) and co-infection.  ...  These range from ligand-based and structure-based virtual screening modelling the proteome of the bacterium.  ...  Acknowledgements LYB and GCM are grateful to Chinhoyi University of Technology for their support in introducing computational drug discovery and development research work at the University and all our  ... 
doi:10.5772/intechopen.82374 fatcat:m246owirwbfwllenxnf64zqzgu

Docking Screens for Novel Ligands Conferring New Biology

John J. Irwin, Brian K. Shoichet
2016 Journal of Medicinal Chemistry  
It is now plausible to dock libraries of 10 million molecules against targets over several days or weeks.  ...  When the molecules screened are commercially available, they may be rapidly tested to find new leads.  ...  A virtual screen discovers novel, fragment-sized inhibitors of Mycobacterium tuberculosis InhA. J. Chem. Inf. Model. 2015; 55:645-659. [PubMed: 25636146] 21.  ... 
doi:10.1021/acs.jmedchem.5b02008 pmid:26913380 pmcid:PMC4865415 fatcat:f5b6zfdmrfd3fe5x5khlbsau5e

Progress in targeting cell envelope biogenesis inMycobacterium tuberculosis

Mary Jackson, Michael R McNeil, Patrick J Brennan
2013 Future Microbiology  
Most of the newly discovered compounds showing promise for the treatment of TB, notably multidrug-resistant TB, inhibit aspects of Mycobacterium tuberculosis cell envelope metabolism.  ...  The advantages of whole cell-versus targetbased screening in the perpetual search for new targets and products to counter multidrug-resistant TB are discussed.  ...  Sacchettini and colleagues discovered that the actual inhibitor of InhA is an INH-NAD adduct [19] .  ... 
doi:10.2217/fmb.13.52 pmid:23841633 pmcid:PMC3867987 fatcat:mwtudhltyreb7bsnxnk537lr2e

In Silico Strategies in Tuberculosis Drug Discovery

Stephani Joy Y. Macalino, Junie B. Billones, Voltaire G. Organo, Maria Constancia O. Carrillo
2020 Molecules  
Tuberculosis (TB) remains a serious threat to global public health, responsible for an estimated 1.5 million mortalities in 2018.  ...  Discovering new and more potent antibiotics that target novel TB protein targets is an attractive strategy towards controlling the global TB epidemic.  ...  Introduction In 1882, Mycobacterium tuberculosis (Mtb) was identified by Robert Koch as the causative agent of tuberculosis (TB), an infectious disease that continuous to be a relevant threat to global  ... 
doi:10.3390/molecules25030665 pmid:32033144 pmcid:PMC7037728 fatcat:wh2uu64av5dndjkb4bhsykgagm

New active leads for tuberculosis booster drugs by structure-based drug discovery

Natalie J. Tatum, John W. Liebeschuetz, Jason C. Cole, Rosangela Frita, Adrien Herledan, Alain R. Baulard, Nicolas Willand, Ehmke Pohl
2017 Organic and biomolecular chemistry  
Three new chemical scaffolds for the inhibition of the transcriptional regulator EthR from M. tuberculosis have been identified and verified by biophysical and biological assays.  ...  NJT is grateful to the CCDC for a pre-doctoral fellowship. We thank E. Dickinson and I.  ...  Edwards for their excellent technical support, the University of Cambridge High Performance Computing for access to their supercomputer, and the Diamond Light Source and their staff for building and maintaining  ... 
doi:10.1039/c7ob00910k pmid:29182187 fatcat:7nomafiw75arjppq246g7fjzka

Early Drug Development and Evaluation of Putative Antitubercular Compounds in the -Omics Era

Alina Minias, Lidia Żukowska, Ewelina Lechowicz, Filip Gąsior, Agnieszka Knast, Sabina Podlewska, Daria Zygała, Jarosław Dziadek
2021 Frontiers in Microbiology  
Mycobacterium tuberculosis is an intracellular pathogen with an unusually thick, waxy cell wall and a complex life cycle.  ...  Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis. According to the WHO, the disease is one of the top 10 causes of death of people worldwide.  ...  Virtual screening is an useful tool to identify new inhibitors for the key cellular components.  ... 
doi:10.3389/fmicb.2020.618168 pmid:33603720 pmcid:PMC7884339 fatcat:zp4b5aqdofekjapuu2otmx2hia

Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Carl A. Machutta, Christopher S. Kollmann, Kenneth E. Lind, Xiaopeng Bai, Pan F. Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S. Besra, David Barros-Aguirre, Robert H. Bates, Paolo A. Centrella (+53 others)
2017 Nature Communications  
This concept was further explored by screening 42 targets from Mycobacterium tuberculosis.  ...  We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT).  ...  Acknowledgements We gratefully acknowledge our collaborators for supplying the purified proteins used in the Tuberculosis screen: Prof. Yuk-Ching Tse-Dinh, Prof. John Blanchard, Prof.  ... 
doi:10.1038/ncomms16081 pmid:28714473 pmcid:PMC5520047 fatcat:fylscunrgrg3lj6tv4fdfiuox4

Predictive Power of In Silico Approach to Evaluate Chemicals against M. tuberculosis: A Systematic Review

Giulia Oliveira Timo, Rodrigo Souza Silva Valle dos Reis, Adriana Françozo de Melo, Thales Viana Labourdette Costa, Pérola de Oliveira Magalhães, Mauricio Homem-de-Mello
2019 Pharmaceuticals  
The following in vitro/vivo analysis showed that, although the virtual assays were able to decrease the number of molecules tested, saving time and money, virtual screening procedures still need to develop  ...  Mycobacterium tuberculosis (Mtb) is an endemic bacterium worldwide that causes tuberculosis (TB) and involves long-term treatment that is not always effective.  ...  Conflicts of Interest: The authors declare no conflict of interest. Pharmaceuticals 2019, 12, 135  ... 
doi:10.3390/ph12030135 pmid:31527425 pmcid:PMC6789803 fatcat:bdmxbkidonaghbrai2bg437o7m

Use of Artificial Intelligence and Machine Learning for Discovery of Drugs for Neglected Tropical Diseases

David A. Winkler
2021 Frontiers in Chemistry  
Neglected tropical diseases continue to create high levels of morbidity and mortality in a sizeable fraction of the world's population, despite ongoing research into new treatments.  ...  Pharmaceutical development business models, cost of developing new drug treatments and subsequent costs to patients, and accessibility of technologies to scientists in most of the affected countries are  ...  publicly available bioassay screens of Mycobacterium tuberculosis inhibitors (Periwal et al., 2011) .  ... 
doi:10.3389/fchem.2021.614073 pmid:33791277 pmcid:PMC8005575 fatcat:obk5rdcpb5eblmghmey63ulztm

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

Luiz Augusto Basso, Luiz Hildebrando Pereira da Silva, Arthur Germano Fett-Neto, Walter Filgueira de Azevedo Junior, Ícaro de Souza Moreira, Mário Sérgio Palma, João Batista Calixto, Spartaco Astolfi Filho, Ricardo Ribeiro dos Santos, Milena Botelho Pereira Soares, Diógenes Santiago Santos
2005 Memórias do Instituto Oswaldo Cruz  
The extension of the country covers a wide range of climates, soil types, and altitudes, providing a unique set of selective pressures for the adaptation of plant life in these scenarios.  ...  compounds active against tuberculosis, malaria, and chronic-degenerative diseases.  ...  A screening for growth inhibition of Mycobacterium tuberculosis using the microplate Alamar blue assay was carried out with 44 plant species previously chosen on the basis of traditional use against tuberculosis  ... 
doi:10.1590/s0074-02762005000600001 fatcat:strs3kz2wzfglar4hfjmjjwobm
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