Chapter 10: Molecular Modelling of Ligand–Macromolecule Complexes

The chapter aims to provide the non-specialist of modelling with a solid overview of the structure-based computational methods available for studying protein ligand complexes. Computational structure based methods are versatile and allow one to obtain information pertinent for different aspects of ligand binding, whether it is the identification of putative binders for a given target, the construction of structures of a ligand-target complex or the prediction or analysis of ligand binding affinities. As a result, they have taken an important role as provider of information complementary to those obtained experimentally and they are now routinely applied at various stages of preclinical drug discovery.

The chapter gives a general introduction to docking, scoring, as well as more advanced free energy prediction methods. It discusses the current scope of the methods, with emphasis on the aspects of the structure that need to be considered in order to obtain reliable predictions. Representative examples were selected to illustrate common applications of the methods. Current challenges and perspective of development are presented.