Related ArticlesThiourea-Based Inhibitors of the B-Cell Lymphoma 6 (BCL6) BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design.
J Med Chem. 2018 Jul 03;:
Authors: Cheng H, Linhares B, Yu W, Cardenas MG, Ai Y, Jiang W, Winkler A, Cohen S, Melnick A, MacKerell AD, Cierpicki T, Xue F
Abstract
Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6BTB) and its co-repressors have emerged as a promising target for anti-cancer therapeutics. However, identification of potent, drug-like inhibitors of the BCL6BTB has remained challenging. Using NMR-based screening of a library of fragment-like small molecules, we have identified a thiourea compound (7CC5) that binds to the BCL6BTB. From this hit, the application of computer-aided drug design (CADD), medicinal chemistry, NMR spectroscopy, and X-ray crystallography has yielded an inhibitor 15f, which demonstrated over 100-fold improved potency for the BCL6BTB. This gain in potency was achieved by a unique binding mode that mimics the binding mode of the corepressor SMRT into the "aromatic" and the "HDCH" sites. The structure-activity relationship based on these new inhibitors will have a significant impact on the rational design of novel BCL6 inhibitors, facilitating the identification of therapeutics for the treatment of BCL6-dependent tumors.
PMID: 29969259 [PubMed - as supplied by publisher]
[NMR paper] Potent inhibitors of Mycobacterium tuberculosis growth identified by using in-cell NMR-based screening.
Potent inhibitors of Mycobacterium tuberculosis growth identified by using in-cell NMR-based screening.
http://www.bionmr.com//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--pubs.acs.org-images-pubmed-acspubs.jpg Related Articles Potent inhibitors of Mycobacterium tuberculosis growth identified by using in-cell NMR-based screening.
ACS Chem Biol. 2018 Jan 23;:
Authors: DeMott CM, Girardin R, Cobbert J, Reverdatto S, Burz DS, McDonough K, Shekhtman A
Abstract
In-cell NMR spectroscopy was used to screen for drugs that disrupt the...
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Senior Research Fellow/Platform Manager (Fragment Based Drug Design) - The Conversation AU
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Senior Research Fellow/Platform Manager (Fragment Based Drug Design)
The Conversation AU
You will also provide specialised expertise in biophysical characterisation of protein-ligand interactions using Nuclear Magnetic Resonance Spectroscopy (NMR), Surface Plasmon Resonance (SPR) and other techniques as necessary. The FBDD Platform ...
Senior Research Fellow/Platform Manager (Fragment Based Drug Design) - The Conversation AU
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[NMR paper] NMR Screening in Fragment-Based Drug Design: A Practical Guide.
NMR Screening in Fragment-Based Drug Design: A Practical Guide.
http://www.bionmr.com//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--production.springer.de-OnlineResources-Logos-springerlink.gif Related Articles NMR Screening in Fragment-Based Drug Design: A Practical Guide.
Methods Mol Biol. 2015;1263:197-208
Authors: Kim HY, Wyss DF
Abstract
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[NMR paper] Computer-Aided Design of Fragment Mixtures for NMR-Based Screening.
Computer-Aided Design of Fragment Mixtures for NMR-Based Screening.
Related Articles Computer-Aided Design of Fragment Mixtures for NMR-Based Screening.
PLoS One. 2013;8(3):e58571
Authors: Arroyo X, Goldflam M, Feliz M, Belda I, Giralt E
Abstract
Fragment-based drug discovery is widely applied both in industrial and in academic screening programs. Several screening techniques rely on NMR to detect binding of a fragment to a target. NMR-based methods are among the most sensitive techniques and have the further advantage of yielding a low...
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NMR Screening and Hit Validation in Fragment Based Drug Discovery.
NMR Screening and Hit Validation in Fragment Based Drug Discovery.
Related Articles NMR Screening and Hit Validation in Fragment Based Drug Discovery.
Curr Top Med Chem. 2010 Sep 2;
Authors: Campos-Olivas R
Over the past three decades nuclear magnetic resonance spectroscopy has been developed into a mature technique for the characterization of interactions of small molecule ligands with their corresponding protein and nucleic acid receptors. In fact, a significant number of industrial and academic laboratories employ NMR for screening small...
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09-03-2010 02:30 PM
[BMNRC community] NMR-based screening: a powerful tool in fragment-based drug discovery
NMR-based screening: a powerful tool in fragment-based drug discovery
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Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 (BCL6) BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design.
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