Journal ArticleDOI
Discovering High-Affinity Ligands for Proteins: SAR by NMR
TLDR
A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands and appears particularly useful in target-directed drug research.Abstract:
A nuclear magnetic resonance (NMR)-based method is described in which small organic molecules that bind to proximal subsites of a protein are identified, optimized, and linked together to produce high-affinity ligands. The approach is called "SAR by NMR" because structure-activity relationships (SAR) are obtained from NMR. With this technique, compounds with nanomolar affinities for the FK506 binding protein were rapidly discovered by tethering two ligands with micromolar affinities. The method reduces the amount of chemical synthesis and time required for the discovery of high-affinity ligands and appears particularly useful in target-directed drug research.read more
Citations
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Journal ArticleDOI
CHARMM: the biomolecular simulation program.
Bernard R. Brooks,Charles L. Brooks,Alexander D. MacKerell,Lennart Nilsson,Robert J. Petrella,Benoît Roux,Youngdo Won,Georgios Archontis,Christian Bartels,Stefan Boresch,Amedeo Caflisch,Leo S. D. Caves,Qiang Cui,Aaron R. Dinner,Michael Feig,Stefan Fischer,Jiali Gao,Milan Hodošček,Wonpil Im,K. Kuczera,Themis Lazaridis,Jianpeng Ma,V. Ovchinnikov,Emanuele Paci,Richard W. Pastor,Carol Beth Post,Jingzhi Pu,M. Schaefer,Bruce Tidor,Richard M. Venable,H. L. Woodcock,Xiongwu Wu,Wei Yang,Darrin M. York,Martin Karplus,Martin Karplus +35 more
TL;DR: An overview of the CHARMM program as it exists today is provided with an emphasis on developments since the publication of the original CHARMM article in 1983.
Journal ArticleDOI
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Tilman Oltersdorf,Steven W. Elmore,Alexander R. Shoemaker,Robert C. Armstrong,David J. Augeri,Barbara A. Belli,Milan Bruncko,Thomas L. Deckwerth,Jürgen Dinges,Philip J. Hajduk,Mary K. Joseph,Shinichi Kitada,Stanley J. Korsmeyer,Stanley J. Korsmeyer,Kunzer Aaron R,Anthony Letai,Chi Li,Michael J. Mitten,David G. Nettesheim,Shi Chung Ng,Paul Nimmer,Jacqueline M. O'Connor,Anatol Oleksijew,Andrew M. Petros,John C. Reed,Wang Shen,Stephen K. Tahir,Craig B. Thompson,Kevin J. Tomaselli,Baole Wang,Wendt Michael D,Haichao Zhang,Stephen W. Fesik,Saul H. Rosenberg +33 more
TL;DR: Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation.
PatentDOI
Core structure of GP41 from the HIV envelope glycoprotein
TL;DR: The crystal structure of this complex, composed of the peptides N36 and C34, is a six-helical bundle that shows striking similarity to the low-pH-induced conformation of influenza hemagglutinin and likely represents the core of fusion-active gp41.
Journal ArticleDOI
Small-molecule inhibitors of protein–protein interactions: progressing towards the dream
Michelle R. Arkin,James A. Wells +1 more
TL;DR: Here, illustrative examples are used to discuss general strategies for addressing the challenges inherent in the discovery and characterization of small-molecule inhibitors of protein–protein interactions.
Journal ArticleDOI
Computational Methods in Drug Discovery
TL;DR: Computer-aided drug discovery/design methods have played a major role in the development of therapeutically important small molecules for over three decades and theory behind the most important methods and recent successful applications are discussed.
References
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Journal ArticleDOI
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes
Jun Liu,Jesse D. Farmer,Willam S. Lane,Jeffrey S. Friedman,Irving L. Weissman,Stuart L. Schreiber +5 more
TL;DR: The results suggest that calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that cyclophilin and FKBP mediate the actions of CsA and Fk506 by forming drug-dependent complexes with and altering the activity of calcineURin-calmodulin.
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Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex
TL;DR: The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant Fk506, has been determined to 1.7 angstroms resolution by x-ray crystallography.
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