- Meeting abstract
- Open Access
An exploration of the 3D chemical space has highlighted a specific shape profile for the compounds intended to inhibit protein-protein interactions
© Kuenemann et al.; licensee BioMed Central Ltd. 2015
Published: 13 February 2015
The vital role of Protein-Protein Interactions (PPI) for Life makes them the subject of a growing number of drug discovery projects. Yet, the specific properties of PPI (often described as flat, large and hydrophobic) require a dramatic paradigm shift in our way to design the small compounds meant to modulate them with therapeutic perspectives. To this end, successful inhibitors of PPI targets (iPPI) may be used to discover what singular properties make this type of inhibitors capable of binding to such intricate surfaces. Among the properties from which lessons could be learnt, the 3D characteristics of iPPI have been pinpointed as essential. Understanding the putative shape profile of iPPI could help the design of a new generation of inhibitors.
Identifying low-molecular-weight iPPI is known to be a difficult task. This has usually been translated into designing compounds with higher size, aromaticity, and hydrophobicity. Yet, lessons are being learnt from iPPI bioactive conformations in an attempt to circumvent this trend. During this analysis, we demonstrated that the capacity to bind a protein-protein interface partially rely on the combination of several structural and electrostatic features including the globularity and the distribution of hydrophilic regions but most importantly of hydrophobic interacting regions. More distinctively, iPPI seem to be characterized by a significantly higher efficiency to bind the hydrophobic patches often present at PPI interfaces. The absence of correlation of this type of property with the hydrophobicity and the size of the compounds could open new ways to design iPPI with improved ligand and lipophilic efficiencies and may allow the scientific community to anticipate an era of more drug-like iPPI.
- Basse MJ, Betzi S, Bourgeas R, Bouzidi S, Chetrit B, Hamon V, Morelli X, Roche P: 2P2Idb: a structural database dedicated to orthosteric modulation of protein-protein interactions. Nucleic acids research. 2013, D824-827. 41 DatabaseGoogle Scholar
- Wang R, Fang X, Lu Y, Wang S: The PDBbind database: collection of binding affinities for protein-ligand complexes with known three-dimensional structures. Journal of medicinal chemistry. 2004, 47 (12): 2977-2980. 10.1021/jm030580l.View ArticlePubMedGoogle Scholar
- Cruciani G, Pastor M, Guba W: VolSurf: a new tool for the pharmacokinetic optimization of lead compounds. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2000, 11 (Suppl 2): S29-39.View ArticleGoogle Scholar
- Labbé CM, Laconde G, Kuenemann MA, Villoutreix BO, Sperandio O: iPPI-DB: a manually curated and interactive database of small non-peptide inhibitors of protein-protein interactions. Drug discovery today. 2013, 18 (19-20): 958-968. 10.1016/j.drudis.2013.05.003.View ArticlePubMedGoogle Scholar
- Pihan E, Colliandre L, Guichou JF, Douguet D: e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment-based drug design. Bioinformatics. 2012, 28 (11): 1540-1541. 10.1093/bioinformatics/bts186.View ArticlePubMedGoogle Scholar
- Liu T, Lin Y, Wen X, Jorissen RN, Gilson MK: BindingDB: a web-accessible database of experimentally determined protein-ligand binding affinities. Nucleic acids research. 2007, D198-201. 35 DatabaseGoogle Scholar
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