Do structurally similar ligands bind in a similar fashion?

Abstract

The scope of the current work is to investigate whether structurally similar ligands bind in a similar fashion by exhaustively analyzing experimental data from the protein database (PDB). The complete PDB was searched for pairs of structurally similar ligands binding to the same biological target. The binding sites of the pairs of proteins complexing structurally similar ligands were found to differ in 83% of the cases. The most recurrent structural change among the pairs involves different water molecule architecture. Side-chain movements are observed in half of the pairs, whereas backbone movements rarely occurred. However, two structurally similar ligands generally confirm a high degree of structural conservation. That is, a majority of the ligand pairs occupy the same region in the binding sites, providing support for the use of shape matching in the drug design process. We allow ourselves to draw general conclusions because our data set consists of ligands with drug-like physicochemical properties complexed to a broad spectrum of different protein classes.