[NMR paper] Discovery of 5,5'-Methylenedi-2,3-Cresotic Acid as a Potent Inhibitor of the Chemotactic Activity of the HMGB1·CXCL12 Heterocomplex Using Virtual Screening and NMR Validation.
Discovery of 5,5'-Methylenedi-2,3-Cresotic Acid as a Potent Inhibitor of the Chemotactic Activity of the HMGB1·CXCL12 Heterocomplex Using Virtual Screening and NMR Validation.
Related ArticlesDiscovery of 5,5'-Methylenedi-2,3-Cresotic Acid as a Potent Inhibitor of the Chemotactic Activity of the HMGB1·CXCL12 Heterocomplex Using Virtual Screening and NMR Validation.
Front Chem. 2020;8:598710
Authors: De Leo F, Quilici G, De Marchis F, Mantonico MV, Bianchi ME, Musco G
Abstract
HMGB1 is a key molecule that both triggers and sustains inflammation following infection or injury, and is involved in a large number of pathologies, including cancer. HMGB1 participates in the recruitment of inflammatory cells, forming a heterocomplex with the chemokine CXCL12 (HMGB1·CXCL12), thereby activating the G-protein coupled receptor CXCR4. Thus, identification of molecules that disrupt this heterocomplex can offer novel pharmacological opportunities to treat inflammation-related diseases. To identify new HMGB1·CXCL12 inhibitors we have performed a study on the ligandability of the single HMG boxes of HMGB1 followed by a virtual screening campaign on both HMG boxes using Zbc Drugs and three different docking programs (Glide, AutoDock Vina, and AutoDock 4.2.6). The best poses in terms of scoring functions, visual inspection, and predicted ADME properties were further filtered according to a pharmacophore model based on known HMGB1 binders and clustered according to their structures. Eight compounds representative of the clusters were tested for HMGB1 binding by NMR. We identified 5,5'-methylenedi-2,3-cresotic acid (2a) as a binder of both HMGB1 and CXCL12; 2a also targets the HMGB1·CXCL12 heterocomplex. In cell migration assays 2a inhibited the chemotactic activity of HMGB1·CXCL12 with IC50 in the subnanomolar range, the best documented up to now. These results pave the way for future structure activity relationship studies to optimize the pharmacological targeting of HMGB1·CXCL12 for anti-inflammatory purposes.
[NMR paper] Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain.
Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain.
Related Articles Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain.
Bioorg Med Chem Lett. 2017 Apr 04;:
Authors: Spiliotopoulos D, Zhu J, Wamhoff EC, Deerain N, Marchand JR, Aretz J, Rademacher C, Caflisch A
Abstract
Overexpression of the CREB-binding protein (CBP), a bromodomain-containing transcription coactivator involved in a variety of cellular processes, has been observed in several types of cancer with a...
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04-16-2017 06:09 PM
[NMR paper] Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments.
Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments.
Discovery of New E-Selectin Inhibitors by Virtual Screening, Fluorescence Binding Assays, and STD NMR Experiments.
ChemMedChem. 2016 Mar 21;
Authors: Barra PA, Jiménez VA, Gavin JA, Daranas AH, Alderete JB
Abstract
E-selectin is an endothelial protein that participates in the adhesion of metastatic cancer cells, and is therefore a relevant target for antitumor therapeutic intervention. In this work, virtual...
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[NMR paper] Discovery and validation of SIRT2 inhibitors based on tenovin-6: use of a ¹H-NMR method to assess deacetylase activity.
Discovery and validation of SIRT2 inhibitors based on tenovin-6: use of a ¹H-NMR method to assess deacetylase activity.
Related Articles Discovery and validation of SIRT2 inhibitors based on tenovin-6: use of a ¹H-NMR method to assess deacetylase activity.
Molecules. 2012;17(10):12206-24
Authors: Pirrie L, McCarthy AR, Major LL, Mork?nait? V, Zubrien? A, Matulis D, Lain S, Lebl T, Westwood NJ
Abstract
The search for potent and selective sirtuin inhibitors continues as chemical tools of this type are of use in helping to assign the function...
Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.
Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.
Related Articles Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR.
Bioorg Med Chem Lett. 2010 Sep 15;
Authors: Petros AM, Huth JR, Oost T, Park CM, Ding H, Wang X, Zhang H, Nimmer P, Mendoza R, Sun C, Mack J, Walter K, Dorwin S, Gramling E, Ladror U, Rosenberg SH, Elmore SW, Fesik SW, Hajduk PJ
The Bcl-2 family of proteins plays a major role in the regulation of apoptosis, or programmed cell death. Overexpression of the anti-apoptotic members of this...
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09-29-2010 08:04 AM
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
[NMR paper] Sequential 1H NMR assignments of kistrin, a potent platelet aggregation inhibitor and
Sequential 1H NMR assignments of kistrin, a potent platelet aggregation inhibitor and glycoprotein IIb-IIIa antagonist.
Related Articles Sequential 1H NMR assignments of kistrin, a potent platelet aggregation inhibitor and glycoprotein IIb-IIIa antagonist.
Biochemistry. 1992 Feb 4;31(4):1031-9
Authors: Adler M, Wagner G
Sequence-specific nuclear magnetic resonances assignments have been obtained for the protons of kistrin. Kistrin is a small naturally occurring snake venom protein that inhibits platelet aggregation by blocking the interaction...
Discovery of 5,5'-Methylenedi-2,3-Cresotic Acid as a Potent Inhibitor of the Chemotactic Activity of the HMGB1·CXCL12 Heterocomplex Using Virtual Screening and NMR Validation.
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