Related ArticlesFragment-Linking Approach Using (19)F NMR Spectroscopy To Obtain Highly Potent and Selective Inhibitors of ?-Secretase.
J Med Chem. 2016 Apr 28;59(8):3732-49
Authors: Jordan JB, Whittington DA, Bartberger MD, Sickmier EA, Chen K, Cheng Y, Judd T
Abstract
Fragment-based drug discovery (FBDD) has become a widely used tool in small-molecule drug discovery efforts. One of the most commonly used biophysical methods in detecting weak binding of fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with (19)F NMR-based methods has been shown to provide several advantages over (1)H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate the utility and power of (19)F-based fragment screening by detailing the identification of a second-site fragment through (19)F NMR screening that binds to a specific pocket of the aspartic acid protease, ?-secretase (BACE-1). The identification of this second-site fragment allowed the undertaking of a fragment-linking approach, which ultimately yielded a molecule exhibiting a more than 360-fold increase in potency while maintaining reasonable ligand efficiency and gaining much improved selectivity over cathepsin-D (CatD). X-ray crystallographic studies of the molecules demonstrated that the linked fragments exhibited binding modes consistent with those predicted from the targeted screening approach, through-space NMR data, and molecular modeling.
Highly efficient residue -selective labeling with isotope-labeled Ile, Leu, and Val using a new auxotrophic E. coli strain
Highly efficient residue -selective labeling with isotope-labeled Ile, Leu, and Val using a new auxotrophic E. coli strain
Abstract
We recently developed a practical protocol for preparing proteins bearing stereo-selectively 13C-methyl labeled leucines and valines, instead of the commonly used 13C-methyl labeled precursors for these amino acids, by E. coli cellular expression. Using this protocol, proteins with any combinations of isotope-labeled or unlabeled Leu and Val residues were prepared, including some that could not be prepared by the...
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[NMR paper] A systematic approach to obtain validated partial least square models for predicting lipoprotein subclasses from serum NMR spectra.
A systematic approach to obtain validated partial least square models for predicting lipoprotein subclasses from serum NMR spectra.
http://www.bionmr.com//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--pubs.acs.org-images-pubmed-acspubs.jpg Related Articles A systematic approach to obtain validated partial least square models for predicting lipoprotein subclasses from serum NMR spectra.
Anal Chem. 2014 Jan 7;86(1):543-50
Authors: Mihaleva VV, van Schalkwijk DB, de Graaf AA, van Duynhoven J, van Dorsten FA, Vervoort J, Smilde A, Westerhuis JA,...
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[NMR paper] Potent ?-secretase inhibitors/modulators interact with Amyloid-? fibrils but do not inhibit fibrillation: A high-resolution NMR study.
Potent ?-secretase inhibitors/modulators interact with Amyloid-? fibrils but do not inhibit fibrillation: A high-resolution NMR study.
Related Articles Potent ?-secretase inhibitors/modulators interact with Amyloid-? fibrils but do not inhibit fibrillation: A high-resolution NMR study.
Biochem Biophys Res Commun. 2014 Apr 16;
Authors: Yesuvadian R, Krishnamoorthy J, Ramamoorthy A, Bhunia A
Abstract
Recently, ?-secretase modulators (GSM) have been shown to interact directly with the amyloid precursor protein (APP) and...
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04-22-2014 03:54 PM
[NMR paper] Thiolactomycin-based ?-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy.
Thiolactomycin-based ?-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy.
http://www.bionmr.com//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-standard-jbc_final.gif Related Articles Thiolactomycin-based ?-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy.
J Biol Chem. 2013 Mar 1;288(9):6045-52
...
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05-10-2013 07:03 PM
[NMR paper] Efficient CO-CA transfer in highly deuterated proteins by band-selective homonuclear cross-polarization
Efficient CO-CA transfer in highly deuterated proteins by band-selective homonuclear cross-polarization
Available online 14 March 2013
Publication year: 2013
Source:Journal of Magnetic Resonance</br>
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Robust and efficient band-selective magnetization transfer between CO and CA spins can be achieved in highly deuterated solid proteins by dipolar-based homonuclear cross polarization. The approach is designed for moderate magic-angle spinning rates and high external magnetic fields where the isotropic chemical shift difference of CO and CA considerably exceeds the...
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[NMR paper] Highly selective excitation in biomolecular NMR by frequency-switched single-transiti
Highly selective excitation in biomolecular NMR by frequency-switched single-transition cross-polarization.
Related Articles Highly selective excitation in biomolecular NMR by frequency-switched single-transition cross-polarization.
J Am Chem Soc. 2002 Mar 13;124(10):2076-7
Authors: Ferrage F, Eykyn TR, Bodenhausen G
A new method for selective excitation in biomolecular NMR uses two-fold single-transition cross-polarization between protons and nitrogen-15 or carbon-13 nuclei. Switching the frequencies between the forward and backward transfer...
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11-24-2010 08:49 PM
Novel Small Molecule Inhibitors of MDR Mycobacterium tuberculosis by NMR Fragment Scr
Novel Small Molecule Inhibitors of MDR Mycobacterium tuberculosis by NMR Fragment Screening of Antigen 85C.
Related Articles Novel Small Molecule Inhibitors of MDR Mycobacterium tuberculosis by NMR Fragment Screening of Antigen 85C.
J Med Chem. 2010 Nov 12;
Authors: Scheich C, Puetter V, Schade M
Protein target-based discovery of novel antibiotics has been largely unsuccessful despite rich genome information. Particularly in need are new antibiotics for tuberculosis, which kills 1.6 million people annually and shows a rapid increase in...
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11-16-2010 04:13 PM
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...