What Can We Learn from Molecular Recognition in Protein–Ligand Complexes for the Design of New Drugs?

TLDR

Noncovalent interactions in protein–ligand complexes are essential for drug discovery, and advances rely on growing structural and chemical data that elucidate binding affinity determinants. This review summarizes recent efforts to deepen understanding of molecular recognition and to develop computational tools that leverage structural and energetic insights for novel ligand design. The authors examine ligand similarity and recognition properties to propose binding modes, and provide an overview of existing methods for designing and selecting novel protein ligands. They analyze putative binding site conformations and attempt predictions of ligand interactions.

Abstract

Abstract The understanding of noncovalent interactions in protein–ligand complexes is essential in modern biochemistry and should contribute toward the discovery of new drugs. In the present review, we summarize recent work aimed at a better understanding of the physical nature of molecular recognition in protein–ligand complexes and also at the development and application of new computational tools that exploit our current knowledge on structural and energetic aspects of protein–ligand interactions in the design of novel ligands. These approaches are based on the exponentially growing amount of information about the geometry of protein structures and the properties of small organic molecules exposed to a structured molecular environment. The various contributions that determine the binding affinity of ligands toward a particular receptor are discussed. Their putative binding site conformations are analyzed, and some predictions are attempted. The similarity of ligands is examined with respect to their recognition properties. This information is used to understand and propose binding modes. In addition, an overview of the existing methods for the design and selection of novel protein ligands is given.