publication . Article . 2014

Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?

Matthias Baud;
Open Access English
  • Published: 01 Jan 2014
Abstract
Modulation of protein−protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with PPI target sites pose significant challenges to fragment binding detection. Here, we investigate the requirements for ligand-based NMR techniques to detect rule-of-three compliant fragments that form part of known high-affinity inhibitors of the PPI between the von Hippel−Lindau protein and the alpha subunit of hypoxia-inducible factor 1 (pVHL:HIF-1α). Careful triaging allowed rescuing weak but specific binding of fragments that wou...
Subjects
free text keywords: NMR fragment screening, protein−protein interactions, binding affinity, G alpha subunit, Isothermal titration calorimetry, Transport protein, Chemistry, Ligand (biochemistry), Druggability, Epitope mapping, Computational biology, Protein–protein interaction, Combinatorial chemistry, Biochemistry, Small molecule, Letter
Funded by
FCT| SFRH/BD/81735/2011
Project
SFRH/BD/81735/2011
BIOPHYSICAL STUDIES OF MULTI-PROTEIN COMPLEXES INTERFACES IN FRAGMENT-BASED DRUG DISCOVERY
  • Funder: Fundação para a Ciência e a Tecnologia, I.P. (FCT)
  • Project Code: SFRH/BD/81735/2011
  • Funding stream: SFRH | Doutoramento
,
EC| DRUGE3CRLS
Project
DRUGE3CRLS
Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases
  • Funder: European Commission (EC)
  • Project Code: 311460
  • Funding stream: FP7 | SP2 | ERC
,
RCUK| DISSECTING AND EXPLOITING MOLECULAR RECOGNITION AT PROTEIN-PROTEIN INTERFACES
Project
  • Funder: Research Council UK (RCUK)
  • Project Code: BB/G023123/1
  • Funding stream: BBSRC
,
EC| PVHL-CRL
Project
PVHL-CRL
Interrogating macromolecular assemblies by using fragment-based small molecule approaches: The multiprotein von Hippel Lindau-E3 ubiquitin ligase complex.
  • Funder: European Commission (EC)
  • Project Code: 275683
  • Funding stream: FP7 | SP3 | PEOPLE
30 references, page 1 of 2

(1) Wells, J. A.; McClendon, C. L. Reaching for High-Hanging Fruit in Drug Discovery at Protein−Protein Interfaces. Nature 2007, 450, 1001−1009.

(2) Thompson, A. D.; Dugan, A.; Gestwicki, J. E.; Mapp, A. K. FineTuning Multiprotein Complexes Using Small Molecules. ACS Chem.

Biol. 2012, 7, 1311−1320.

(3) Smith, M. C.; Gestwicki, J. E. Features of Protein−Protein Interactions That Translate Into Potent Inhibitors: Topology, Surface Area and Affinity. Expert Rev. Mol. Med. 2012, 14, e16.

(4) Levy, E. D.; Pereira-Leal, J. B. Evolution and Dynamics of Protein Interactions and Networks. Curr. Opin. Struct. Biol. 2008, 18, 349−357.

(5) Mullard, A. Protein−Protein Interaction Inhibitors Get into the Groove. Nat. Rev. Drug Discovery 2012, 11, 173−175.

(6) Thiel, P.; Kaiser, M.; Ottmann, C. Small-Molecule Stabilization of Protein−Protein Interactions: an Underestimated Concept in Drug Discovery? Angew. Chem., Int. Ed. 2012, 51, 2012−2018.

(7) Fry, D. C. Protein−Protein Interactions as Targets for Small Molecule Drug Discovery. Biopolymers 2006, 84, 535−552.

(8) Immekus, F.; Barandun, L. J.; Betz, M.; Debaene, F.; Petiot, S.; Sanglier-Cianferani, S.; Reuter, K.; Diederich, F.; Klebe, G. Launching Spiking Ligands Into a Protein−Protein Interface: a Promising Strategy to Destabilize and Break Interface Formation in a tRNA Modifying Enzyme. ACS Chem. Biol. 2013, 8, 1163−1178. [OpenAIRE]

(9) Fuller, J. C.; Burgoyne, N. J.; Jackson, R. M. Predicting Druggable Binding Sites at the Protein−Protein Interface. Drug Discovery Today 2009, 14, 155−161.

(10) Higueruelo, A. P.; Schreyer, A.; Bickerton, G. R. J.; Pitt, W. R.; Groom, C. R.; Blundell, T. L. Atomic Interactions and Profile of Small Molecules Disrupting Protein−Protein Interfaces: the TIMBAL Database. Chem. Biol. Drug Des. 2009, 74, 457−467. [OpenAIRE]

(11) Edfeldt, F. N. B.; Folmer, R. H. A.; Breeze, A. L. Fragment Screening to Predict Druggability (Ligandability) and Lead Discovery Success. Drug Discovery Today 2011, 16, 284−287. [OpenAIRE]

(12) Surade, S.; Blundell, T. L. Structural Biology and Drug Discovery of Difficult Targets: the Limits of Ligandability. Chem. Biol. 2012, 19, 42−50. [OpenAIRE]

(13) Schmidtke, P.; Le Guilloux, V.; Maupetit, J.; Tuffeŕy, P. Fpocket: Online Tools for Protein Ensemble Pocket Detection and Tracking.

Nucleic Acids Res. 2010, 38, W582−9.

30 references, page 1 of 2
Abstract
Modulation of protein−protein interactions (PPIs) with small molecules has been hampered by a lack of lucid methods capable of reliably identifying high-quality hits. In fragment screening, the low ligand efficiencies associated with PPI target sites pose significant challenges to fragment binding detection. Here, we investigate the requirements for ligand-based NMR techniques to detect rule-of-three compliant fragments that form part of known high-affinity inhibitors of the PPI between the von Hippel−Lindau protein and the alpha subunit of hypoxia-inducible factor 1 (pVHL:HIF-1α). Careful triaging allowed rescuing weak but specific binding of fragments that wou...
Subjects
free text keywords: NMR fragment screening, protein−protein interactions, binding affinity, G alpha subunit, Isothermal titration calorimetry, Transport protein, Chemistry, Ligand (biochemistry), Druggability, Epitope mapping, Computational biology, Protein–protein interaction, Combinatorial chemistry, Biochemistry, Small molecule, Letter
Funded by
FCT| SFRH/BD/81735/2011
Project
SFRH/BD/81735/2011
BIOPHYSICAL STUDIES OF MULTI-PROTEIN COMPLEXES INTERFACES IN FRAGMENT-BASED DRUG DISCOVERY
  • Funder: Fundação para a Ciência e a Tecnologia, I.P. (FCT)
  • Project Code: SFRH/BD/81735/2011
  • Funding stream: SFRH | Doutoramento
,
EC| DRUGE3CRLS
Project
DRUGE3CRLS
Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases
  • Funder: European Commission (EC)
  • Project Code: 311460
  • Funding stream: FP7 | SP2 | ERC
,
RCUK| DISSECTING AND EXPLOITING MOLECULAR RECOGNITION AT PROTEIN-PROTEIN INTERFACES
Project
  • Funder: Research Council UK (RCUK)
  • Project Code: BB/G023123/1
  • Funding stream: BBSRC
,
EC| PVHL-CRL
Project
PVHL-CRL
Interrogating macromolecular assemblies by using fragment-based small molecule approaches: The multiprotein von Hippel Lindau-E3 ubiquitin ligase complex.
  • Funder: European Commission (EC)
  • Project Code: 275683
  • Funding stream: FP7 | SP3 | PEOPLE
30 references, page 1 of 2

(1) Wells, J. A.; McClendon, C. L. Reaching for High-Hanging Fruit in Drug Discovery at Protein−Protein Interfaces. Nature 2007, 450, 1001−1009.

(2) Thompson, A. D.; Dugan, A.; Gestwicki, J. E.; Mapp, A. K. FineTuning Multiprotein Complexes Using Small Molecules. ACS Chem.

Biol. 2012, 7, 1311−1320.

(3) Smith, M. C.; Gestwicki, J. E. Features of Protein−Protein Interactions That Translate Into Potent Inhibitors: Topology, Surface Area and Affinity. Expert Rev. Mol. Med. 2012, 14, e16.

(4) Levy, E. D.; Pereira-Leal, J. B. Evolution and Dynamics of Protein Interactions and Networks. Curr. Opin. Struct. Biol. 2008, 18, 349−357.

(5) Mullard, A. Protein−Protein Interaction Inhibitors Get into the Groove. Nat. Rev. Drug Discovery 2012, 11, 173−175.

(6) Thiel, P.; Kaiser, M.; Ottmann, C. Small-Molecule Stabilization of Protein−Protein Interactions: an Underestimated Concept in Drug Discovery? Angew. Chem., Int. Ed. 2012, 51, 2012−2018.

(7) Fry, D. C. Protein−Protein Interactions as Targets for Small Molecule Drug Discovery. Biopolymers 2006, 84, 535−552.

(8) Immekus, F.; Barandun, L. J.; Betz, M.; Debaene, F.; Petiot, S.; Sanglier-Cianferani, S.; Reuter, K.; Diederich, F.; Klebe, G. Launching Spiking Ligands Into a Protein−Protein Interface: a Promising Strategy to Destabilize and Break Interface Formation in a tRNA Modifying Enzyme. ACS Chem. Biol. 2013, 8, 1163−1178. [OpenAIRE]

(9) Fuller, J. C.; Burgoyne, N. J.; Jackson, R. M. Predicting Druggable Binding Sites at the Protein−Protein Interface. Drug Discovery Today 2009, 14, 155−161.

(10) Higueruelo, A. P.; Schreyer, A.; Bickerton, G. R. J.; Pitt, W. R.; Groom, C. R.; Blundell, T. L. Atomic Interactions and Profile of Small Molecules Disrupting Protein−Protein Interfaces: the TIMBAL Database. Chem. Biol. Drug Des. 2009, 74, 457−467. [OpenAIRE]

(11) Edfeldt, F. N. B.; Folmer, R. H. A.; Breeze, A. L. Fragment Screening to Predict Druggability (Ligandability) and Lead Discovery Success. Drug Discovery Today 2011, 16, 284−287. [OpenAIRE]

(12) Surade, S.; Blundell, T. L. Structural Biology and Drug Discovery of Difficult Targets: the Limits of Ligandability. Chem. Biol. 2012, 19, 42−50. [OpenAIRE]

(13) Schmidtke, P.; Le Guilloux, V.; Maupetit, J.; Tuffeŕy, P. Fpocket: Online Tools for Protein Ensemble Pocket Detection and Tracking.

Nucleic Acids Res. 2010, 38, W582−9.

30 references, page 1 of 2
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