posted on 2012-09-24, 00:00authored byNoé Sturm, Jérémy Desaphy, Ronald J. Quinn, Didier Rognan, Esther Kellenberger
Selectivity is a key factor in drug development. In this
paper,
we questioned the Protein Data Bank to better understand the reasons
for the promiscuity of bioactive compounds. We assembled a data set
of >1000 pairs of three-dimensional structures of complexes between
a “drug-like” ligand (as its physicochemical properties
overlap that of approved drugs) and two distinct “druggable”
protein targets (as their binding sites are likely to accommodate
“drug-like” ligands). 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 many ligands can adapt to different protein environments
by changing their conformation, by using different chemical moieties
to anchor to different targets, or by adopting unusual extreme binding
modes (e.g., only apolar contact between the ligand and the protein,
even though polar groups are present on the ligand or at the protein
surface). Lastly, we provided new elements in support to the recent
studies which suggest that the promiscuity of a ligand might be inferred
from its molecular complexity.