Related ArticlesAn NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor.
Molecules. 2016;21(7)
Authors: Khattri RB, Morris DL, Davis CM, Bilinovich SM, Caras AJ, Panzner MJ, Debord MA, Leeper TC
Abstract
Selective hits for the glutaredoxin ortholog of Brucella melitensis are determined using STD NMR and verified by trNOE and (15)N-HSQC titration. The most promising hit, RK207, was docked into the target molecule using a scoring function to compare simulated poses to experimental data. After elucidating possible poses, the hit was further optimized into the lead compound by extension with an electrophilic acrylamide warhead. We believe that focusing on selectivity in this early stage of drug discovery will limit cross-reactivity that might occur with the human ortholog as the lead compound is optimized. Kinetics studies revealed that lead compound 5 modified with an ester group results in higher reactivity than an acrylamide control; however, after modification this compound shows little selectivity for bacterial protein versus the human ortholog. In contrast, hydrolysis of compound 5 to the acid form results in a decrease in the activity of the compound. Together these results suggest that more optimization is warranted for this simple chemical scaffold, and opens the door for discovery of drugs targeted against glutaredoxin proteins-a heretofore untapped reservoir for antibiotic agents.
PMID: 27438815 [PubMed - as supplied by publisher]
[NMR paper] Synthesis, spectroscopic investigations (X-ray, NMR and TD-DFT), antimicrobial activity and molecular docking of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone.
Synthesis, spectroscopic investigations (X-ray, NMR and TD-DFT), antimicrobial activity and molecular docking of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone.
Related Articles Synthesis, spectroscopic investigations (X-ray, NMR and TD-DFT), antimicrobial activity and molecular docking of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone.
Molecules. 2015;20(7):13240-63
Authors: Barakat A, Ghabbour HA, Al-Majid AM, Soliman SM, Ali M, Mabkhot YN, Shaik MR, Fun HK
Abstract
The synthesis of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone 1...
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[NMR paper] High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH.
High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH.
High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH.
ChemMedChem. 2015 Nov 23;
Authors: Bottini A, Wu B, Barile E, De SK, Leone M, Pellecchia M
Abstract
Recently we described a novel approach, named high-throughput screening (HTS) by NMR that allows the identification, from large combinatorial peptide libraries, of potent and selective...
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[NMR paper] Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.
Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.
http://www.bionmr.com//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-custom-pnas_full.gif Related Articles Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients.
Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17504-9
Authors: Wang CK, Northfield SE, Colless B, Chaousis S, Hamernig I, Lohman RJ, Nielsen DS, Schroeder CI, Liras S, Price...
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[NMR paper] Accounting for Conformational Variability in Protein-Ligand Docking with NMR-Guided Rescoring.
Accounting for Conformational Variability in Protein-Ligand Docking with NMR-Guided Rescoring.
Related Articles Accounting for Conformational Variability in Protein-Ligand Docking with NMR-Guided Rescoring.
J Am Chem Soc. 2013 Apr 8;
Authors: Skjærven L, Codutti L, Angelini A, Grimaldi M, Latek D, Monecke P, Dreyer MK, Carlomagno T
Abstract
A key component to success in structure-based drug design is reliable information on protein-ligand interactions. Recent development in NMR techniques has accelerated this process by overcoming some of...
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Accounting for Conformational Variability in Protein–Ligand Docking with NMR-Guided Rescoring
Accounting for Conformational Variability in Protein–Ligand Docking with NMR-Guided Rescoring
Lars Skjærven, Luca Codutti, Andrea Angelini, Manuela Grimaldi, Dorota Latek, Peter Monecke, Matthias K. Dreyer and Teresa Carlomagno
http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/0/jacsat.ahead-of-print/ja4007468/aop/images/medium/ja-2013-007468_0009.gif
Journal of the American Chemical Society
DOI: 10.1021/ja4007468
http://feeds.feedburner.com/~ff/acs/jacsat?d=yIl2AUoC8zA
http://feeds.feedburner.com/~r/acs/jacsat/~4/39zhOcXGgnI
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Protein-ligand docking guided by ligand pharmacophore-mapping experiment by NMR.
Protein-ligand docking guided by ligand pharmacophore-mapping experiment by NMR.
Protein-ligand docking guided by ligand pharmacophore-mapping experiment by NMR.
J Mol Graph Model. 2011 Sep 3;
Authors: Fukunishi Y, Mizukoshi Y, Takeuchi K, Shimada I, Takahashi H, Nakamura H
Abstract
We developed a new protein-ligand docking calculation method using experimental NMR data. Recently, we proposed a novel ligand epitope-mapping experiment, which utilizes the difference between the longitudinal relaxation rates of ligand protons with and...
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Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.
Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.
Target immobilization as a strategy for NMR-based fragment screening: comparison of TINS, STD, and SPR for fragment hit identification.
J Biomol Screen. 2010 Sep;15(8):978-89
Authors: Kobayashi M, Retra K, Figaroa F, Hollander JG, Ab E, Heetebrij RJ, Irth H, Siegal G
Fragment-based drug discovery (FBDD) has become a widely accepted tool that is complementary to high-throughput screening (HTS) in developing...
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[NMR paper] NMR-restrained docking of a peptidic inhibitor to the N-terminal domain of the phosph
NMR-restrained docking of a peptidic inhibitor to the N-terminal domain of the phosphoenolpyruvate:sugar phosphotransferase enzyme I.
Related Articles NMR-restrained docking of a peptidic inhibitor to the N-terminal domain of the phosphoenolpyruvate:sugar phosphotransferase enzyme I.
J Comput Aided Mol Des. 2001 Feb;15(2):103-15
Authors: Rognan D, Mukhija S, Folkers G, Zerbe O
Starting from the NMR structure of the binary complex between the N-terminal domain of the unphosphorylated enzyme I (EIN) of the phosphoenolpyruvate:sugar...
An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor.
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