Use of secondary structure element information in drug design: polypharmacology and conserved motifs in protein–ligand binding and protein–protein interfaces

Abstract

The structure-based design of small-molecule inhibitors of protein–ligand and protein–protein interfaces is a key component of drug discovery. The underlying protein interactions can be regarded based on structural similarity of the secondary structure elements: similarities around the binding site (‘ligand-sensing cores’) or in the protein interface (‘interface-sensing surfaces’) in otherwise unrelated proteins can be useful in predicting polypharmacology and identifying new lead structures. Even small conserved motifs can provide similar interaction patterns in proteins with a completely different fold and function. The identification of these structural similarities can help in the design of new drugs by guiding further optimization. Here, the concepts and ideas based on secondary structure element similarities and their successful applications in drug design are reviewed and discussed.