A general analysis of the molecular descriptors of the small molecule modulators present in the 2P2I database led us to define a general profile for these compounds. We have proposed a ‘Rule-of-Four’ as a guideline to characterize this particular chemical space.
- - Are bigger than current drugs (av. MW ≥ 400 Da)
- Have more rings (~4 in average)
- Have more hydrogen bond acceptors
- Are more hydrophobic (average alogP ~4)
Using more thorough statistical and learning machine analyses we are now ready to provide new tools to achieve higher confidence evaluation of small chemical compounds as orthosteric PPII modulators. The ultimate goal is to propose to the scientific community a way to filter proprietary chemical libraries
to design PPI-targeted libraries.
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- - Morelli X, Bourgeas R, Roche P: Chemical and structural lessons from recent successes in protein-protein interaction inhibition (2P2I). Curr Opin Chem Biol 2011, 15:475-481.Pubmed ID: 21684802