Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions

Brooke Bullock Lao, Kevin Drew, Danielle A. Guarracino, Thomas F. Brewer, Daniel W. Heindel, Richard Bonneau, Paramjit S. Arora

Research output: Contribution to journalArticle

Abstract

Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Experimental screening of focused compound libraries is used to further optimize inhibitors but the number of possible designs that can be efficiently synthesized and experimentally tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein-protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein-protein interactions.

Original languageEnglish (US)
Pages (from-to)7877-7888
Number of pages12
JournalJournal of the American Chemical Society
Volume136
Issue number22
DOIs
StatePublished - Jun 4 2014

Fingerprint

Proteins
Libraries
Peptidomimetics
Binding energy
Scaffolds
Amino acids
Screening
Ligands
Amino Acids
Molecules

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions. / Lao, Brooke Bullock; Drew, Kevin; Guarracino, Danielle A.; Brewer, Thomas F.; Heindel, Daniel W.; Bonneau, Richard; Arora, Paramjit S.

In: Journal of the American Chemical Society, Vol. 136, No. 22, 04.06.2014, p. 7877-7888.

Research output: Contribution to journalArticle

Lao, Brooke Bullock ; Drew, Kevin ; Guarracino, Danielle A. ; Brewer, Thomas F. ; Heindel, Daniel W. ; Bonneau, Richard ; Arora, Paramjit S. / Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions. In: Journal of the American Chemical Society. 2014 ; Vol. 136, No. 22. pp. 7877-7888.
@article{55a80f70dfb54f49be5ac71aee176a23,
title = "Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions",
abstract = "Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed {"}hotspot residues{"}, have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Experimental screening of focused compound libraries is used to further optimize inhibitors but the number of possible designs that can be efficiently synthesized and experimentally tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein-protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein-protein interactions.",
author = "Lao, {Brooke Bullock} and Kevin Drew and Guarracino, {Danielle A.} and Brewer, {Thomas F.} and Heindel, {Daniel W.} and Richard Bonneau and Arora, {Paramjit S.}",
year = "2014",
month = "6",
day = "4",
doi = "10.1021/ja502310r",
language = "English (US)",
volume = "136",
pages = "7877--7888",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "22",

}

TY - JOUR

T1 - Rational design of topographical helix mimics as potent inhibitors of protein-protein interactions

AU - Lao, Brooke Bullock

AU - Drew, Kevin

AU - Guarracino, Danielle A.

AU - Brewer, Thomas F.

AU - Heindel, Daniel W.

AU - Bonneau, Richard

AU - Arora, Paramjit S.

PY - 2014/6/4

Y1 - 2014/6/4

N2 - Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Experimental screening of focused compound libraries is used to further optimize inhibitors but the number of possible designs that can be efficiently synthesized and experimentally tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein-protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein-protein interactions.

AB - Protein-protein interactions encompass large surface areas, but often a handful of key residues dominate the binding energy landscape. Rationally designed small molecule scaffolds that reproduce the relative positioning and disposition of important binding residues, termed "hotspot residues", have been shown to successfully inhibit specific protein complexes. Although this strategy has led to development of novel synthetic inhibitors of protein complexes, often direct mimicry of natural amino acid residues does not lead to potent inhibitors. Experimental screening of focused compound libraries is used to further optimize inhibitors but the number of possible designs that can be efficiently synthesized and experimentally tested in academic settings is limited. We have applied the principles of computational protein design to optimization of nonpeptidic helix mimics as ligands for protein complexes. We describe the development of computational tools to design helix mimetics from canonical and noncanonical residue libraries and their application to two therapeutically important protein-protein interactions: p53-MDM2 and p300-HIF1α. The overall study provides a streamlined approach for discovering potent peptidomimetic inhibitors of protein-protein interactions.

UR - http://www.scopus.com/inward/record.url?scp=84901937652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901937652&partnerID=8YFLogxK

U2 - 10.1021/ja502310r

DO - 10.1021/ja502310r

M3 - Article

C2 - 24972345

AN - SCOPUS:84901937652

VL - 136

SP - 7877

EP - 7888

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 22

ER -