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DC Field | Value | Language |
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dc.citation.endPage | 16212 | - |
dc.citation.number | 50 | - |
dc.citation.startPage | 16206 | - |
dc.citation.title | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | - |
dc.citation.volume | 128 | - |
dc.contributor.author | Park, Cheol-Min | - |
dc.contributor.author | Oie, Tetsuro | - |
dc.contributor.author | Petros, Andrew M. | - |
dc.contributor.author | Zhang, Haichao | - |
dc.contributor.author | Nimmer, Paul M. | - |
dc.contributor.author | Henry, Rodger F. | - |
dc.contributor.author | Elmore, Steven W. | - |
dc.date.accessioned | 2023-12-22T09:39:20Z | - |
dc.date.available | 2023-12-22T09:39:20Z | - |
dc.date.created | 2014-11-10 | - |
dc.date.issued | 2006-12 | - |
dc.description.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. | - |
dc.identifier.bibliographicCitation | JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.128, no.50, pp.16206 - 16212 | - |
dc.identifier.doi | 10.1021/ja0650347 | - |
dc.identifier.issn | 0002-7863 | - |
dc.identifier.scopusid | 2-s2.0-33845570247 | - |
dc.identifier.uri | https://scholarworks.unist.ac.kr/handle/201301/8555 | - |
dc.identifier.url | http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=33845570247 | - |
dc.identifier.wosid | 000242825600080 | - |
dc.language | 영어 | - |
dc.publisher | AMER CHEMICAL SOC | - |
dc.title | Design, synthesis, and computational studies of inhibitors of Bcl-X-L | - |
dc.type | Article | - |
dc.description.journalRegisteredClass | scopus | - |
dc.subject.keywordPlus | PI | - |
dc.subject.keywordPlus | DOT-CENTER-DOT | - |
dc.subject.keywordPlus | MACROCYCLIC INHIBITORS | - |
dc.subject.keywordPlus | PROTEIN-LIGAND | - |
dc.subject.keywordPlus | HYDROGEN-BONDS | - |
dc.subject.keywordPlus | FAMILY | - |
dc.subject.keywordPlus | CONFORMATION | - |
dc.subject.keywordPlus | PEPTIDE | - |
dc.subject.keywordPlus | BINDING | - |
dc.subject.keywordPlus | DEATH | - |
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