Selectivity is an important issue in drug development.To better understand the reasons why bioactive compounds bind to different proteins, we identified in the Protein Databank 247 �drug-like� ligands in complex with two or more distinct protein targets.Studying the similarity between the ligand-binding sites in the different targets revealed that the lack of selectivity of a ligand can be due (i) to the fact that Nature has created the same binding pocket in different proteins which do not necessarily have otherwise sequence or fold similarity, or (ii) to specific characteristics of the ligand itself.In particular, we demonstrated that ligands can adapt to different protein environments by changing their conformation, or by using different chemical moieties to anchor to different targets, or by adopting unusual binding modes.Lastly, we suggested possible relationships between structure and promiscuity. The above figure gives an example of promiscuous ligand: the three-dimensional structure of the inhibitor sb220025 in complex with two different map kinases, p38 (PDB: 1bl7) and erk2 (PDB: 3erk).

Ligand promiscuity or protein redundancy?: Lessons from the PDB

246th National Meeting (2013)

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