IDPs (intrinsically disordered proteins) play crucial roles in many important cellular processes such as signalling or transcription and are attractive therapeutic targets for several diseases. The considerable structural flexibility of IDPs poses a challenge for rational drug discovery approaches. Consequently, structure-based drug design efforts to date have mostly focused on inhibiting interactions of IDPs with other proteins whose structure can be solved by conventional biophysical methods. Yet, in recent years, several examples of small molecules that bind to monomeric IDPs in their disordered states have been reported, suggesting that this approach may offer new opportunities for therapeutic interventions. Further developments of this strategy will greatly benefit from an improved understanding of molecular recognition mechanisms between small molecules and IDPs. The present article summarizes findings from experimental and computational studies of the mechanisms of interaction between small molecules and three IDPs in their disordered states: c-Myc, Aβ (amyloid β-peptide) and α-synuclein.
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October 2012
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Conference Article|
September 19 2012
Mechanisms of small-molecule binding to intrinsically disordered proteins
Rémi Cuchillo;
Rémi Cuchillo
1EaStCHEM School of Chemistry, Joseph Black Building, The King's Buildings, University of Edinburgh, Edinburgh EH9 3JJ, U.K.
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Julien Michel
Julien Michel
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1To whom correspondence should be addressed (emailjulien.michel@ed.ac.uk).
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Biochem Soc Trans (2012) 40 (5): 1004–1008.
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Received:
April 11 2012
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Rémi Cuchillo, Julien Michel; Mechanisms of small-molecule binding to intrinsically disordered proteins. Biochem Soc Trans 1 October 2012; 40 (5): 1004–1008. doi: https://doi.org/10.1042/BST20120086
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