title: Rigorous Free Energy Calculations in Structure-Based Drug Design.
abstract: Structure-based drug design could benefit greatly from computational methodologies that accurately predict the binding affinity of small compounds to target biomolecules. However, the current scoring functions used to rank compounds in virtual screens by docking are not sufficiently accurate to guide reliably the design of tight binding ligands. Thus, there is strong interest in methodologies based on molecular simulations of protein-ligand complexes which are perceived to be more accurate and, with advances in computing power, amenable to routine use. This report provides an overview of the technical details necessary to understand, execute and analyze binding free energy calculations, using free energy perturbation or thermodynamic integration methods. Examples of possible applications in structure-based drug design are discussed. Current methodological limitations are highlighted as well as a number of ongoing developments to improve the scope, reliability, and practicalities of free energy calculations. These efforts are paving the way for a more common use of free energy calculations in molecular design.
authors.affiliation: Institute of Structural and Molecular Biology, The University of Edinburgh, Edinburgh, EH9 3JR, UK. mail@julienmichel.net.|Department of Chemistry, Yale University, New Haven, CT-06520, USA. mail@julienmichel.net.
authors.forename: Julien
authors.initials: J
authors.lastname: Michel
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Cambridge, CB21 6GB, UK.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Foloppe
authors.affiliation: School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Essex
keywords: Binding affinity; Drug design; Free energy perturbation; Molecular recognition; Thermodynamic integration