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  Increasing the Efficiency of Ligands for FK506-Binding Protein 51 by Conformational Control

Wang, Y., Kirschner, A., Fabian, A.-K., Gopalakrishnan, R., Kress, C., Hoogeland, B., et al. (2013). Increasing the Efficiency of Ligands for FK506-Binding Protein 51 by Conformational Control. JOURNAL OF MEDICINAL CHEMISTRY, 56(10), 3922-3935. doi:10.1021/jm400087k.

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 Creators:
Wang, Yansong1, Author
Kirschner, Alexander1, Author
Fabian, Anne-Katrin1, Author
Gopalakrishnan, Ranganath2, Author           
Kress, Christoph1, Author
Hoogeland, Bastiaan1, Author
Koch, Uwe1, Author
Kozany, Christian2, Author           
Bracher, Andreas3, Author           
Hausch, Felix2, Author           
Affiliations:
1external, ou_persistent22              
2AG Hausch, Felix, Florian Holsboer (Direktor), Max Planck Institute of Psychiatry, Max Planck Society, ou_1607148              
3Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: PURINE NUCLEOSIDE PHOSPHORYLASE; ENTHALPY-ENTROPY COMPENSATION; TRANSITION-STATE ANALOGS; MEDICINAL CHEMISTRY; CRYSTAL-STRUCTURES; DRUG DISCOVERY; BINDING; COMPLEXES; DESIGN; FKBP12
 Abstract: The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr(113) that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51.

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Language(s): eng - English
 Dates: 2013
 Publication Status: Issued
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000319650100012
DOI: 10.1021/jm400087k
 Degree: -

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Title: JOURNAL OF MEDICINAL CHEMISTRY
Source Genre: Journal
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Publ. Info: 1155 16TH ST, NW, WASHINGTON, DC 20036 USA : AMER CHEMICAL SOC
Pages: - Volume / Issue: 56 (10) Sequence Number: - Start / End Page: 3922 - 3935 Identifier: ISSN: 0022-2623