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Rigorous free energy calculations in structure-based drug design

Rigorous free energy calculations in structure-based drug design
Rigorous free energy calculations in structure-based drug design
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.

molecular recognition, binding affinity, drug design, free energy perturbation, thermodynamic integration
1868-1743
570-578
Michel, Julien
3dfda20a-a6fa-4214-8c7d-578f550b9ad7
Foloppe, Nicolas
949752f4-2b51-488b-a332-66842cdfb0c8
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Michel, Julien
3dfda20a-a6fa-4214-8c7d-578f550b9ad7
Foloppe, Nicolas
949752f4-2b51-488b-a332-66842cdfb0c8
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

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

Record type: Article

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.

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More information

Published date: 17 September 2010
Keywords: molecular recognition, binding affinity, drug design, free energy perturbation, thermodynamic integration

Identifiers

Local EPrints ID: 179869
URI: http://eprints.soton.ac.uk/id/eprint/179869
ISSN: 1868-1743
PURE UUID: ea8ea43b-d525-46fc-bc7f-90559d997973
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 06 Apr 2011 09:29
Last modified: 03 Dec 2019 02:02

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