BROWSE

Related Researcher

Author's Photo

Park, Cheol-Min
Synthetic & Medicinal Chemistry Lab
Research Interests
  • Organic synthesis, medicinal chemistry, chemical biology

ITEM VIEW & DOWNLOAD

Design, synthesis, and computational studies of inhibitors of Bcl-X-L

Cited 19 times inthomson ciCited 21 times inthomson ci
Title
Design, synthesis, and computational studies of inhibitors of Bcl-X-L
Author
Park, Cheol-MinOie, TetsuroPetros, Andrew M.Zhang, HaichaoNimmer, Paul M.Henry, Rodger F.Elmore, Steven W.
Keywords
Binding affinity; Global energy; Inhibition constant; Protein inhibitors; Steric interactions
Issue Date
2006-12
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.128, no.50, pp.16206 - 16212
Abstract
One of the primary objectives in the design of protein inhibitors is to shape the three-dimensional structures of small molecules to be complementary to the binding site of a target protein. In the course of our efforts to discover potent inhibitors of Bcl-2 family proteins, we found a unique folded conformation adopted by tethered aromatic groups in the ligand that significantly enhanced binding affinity to Bcl-X L. This finding led us to design compounds that were biased by nonbonding interactions present in a urea tether to adopt this bioactive, folded motif. To characterize the key interactions that induce the desired conformational bias, a series of substituted N,N-diarylureas were prepared and analyzed using X-ray crystallography and quantum mechanical calculations. Stabilizing π-stacking interactions and destabilizing steric interactions were predicted to work in concert in two of the substitution patterns to promote the bioactive conformation as a global energy minimum and result in a high target binding affinity. Conversely, intramolecular hydrogen bonding present in the third substitution motif promotes a less active, extended conformer as the energetically favored geometry. These findings were corroborated when the inhibition constant of binding to BcL-X L was determined for fully elaborated analogues bearing these structural motifs. Finally, we obtained the NMR solution structure of the disubstituted N,N-diarylurea bound to Bcl-X L demonstrating the folded conformation of the urea motif engaged in extensive π-interactions with the protein.
URI
Go to Link
DOI
10.1021/ja0650347
ISSN
0002-7863
Appears in Collections:
PHY_Journal Papers
Files in This Item:
2-s2.0-33845570247.pdf Download

find_unist can give you direct access to the published full text of this article. (UNISTARs only)

Show full item record

qrcode

  • mendeley

    citeulike

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

MENU