Rigorous free energy calculations in structure-based drug design

Michel, Julien, Foloppe, Nicolas and Essex, Jonathan W. (2010) Rigorous free energy calculations in structure-based drug design Molecular Informatics, 29, (8-9), pp. 570-578. (doi:10.1002/minf.201000051).


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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.

Item Type: Article
Digital Object Identifier (DOI): doi:10.1002/minf.201000051
ISSNs: 1868-1743 (print)
Keywords: molecular recognition, binding affinity, drug design, free energy perturbation, thermodynamic integration

ePrint ID: 179869
Date :
Date Event
17 September 2010Published
Date Deposited: 06 Apr 2011 09:29
Last Modified: 18 Apr 2017 02:33
Further Information:Google Scholar
URI: http://eprints.soton.ac.uk/id/eprint/179869

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