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Water molecules at protein-drug interfaces: computational prediction and analysis methods

Water molecules at protein-drug interfaces: computational prediction and analysis methods
Water molecules at protein-drug interfaces: computational prediction and analysis methods

The fundamental importance of water molecules at drug-protein interfaces is now widely recognised and a significant feature in structure-based drug design. Experimental methods for analysing the role of water in drug binding have many challenges, including the accurate location of bound water molecules in crystal structures, and problems in resolving specific water contributions to binding thermodynamics. Computational analyses of binding site water molecules provide an alternative, and in principle complete, structural and thermodynamic picture, and their use is now commonplace in the pharmaceutical industry. In this review, we describe the computational methodologies that are available and discuss their strengths and weaknesses. Additionally, we provide a critical analysis of the experimental data used to validate the methods, regarding the type and quality of experimental structural data. We also discuss some of the fundamental difficulties of each method and suggest directions for future study.

0306-0012
9104-9120
Samways, Marley, Luke
75cda5aa-31ef-4f62-9ea3-8655ea55d3fb
Taylor, Richard D.
141004d4-95a6-44f1-93ce-ca36c1b34d61
Bruce Macdonald, Hannah
8e3f96bf-6806-4dc9-bd25-5b7a5325c7a7
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Samways, Marley, Luke
75cda5aa-31ef-4f62-9ea3-8655ea55d3fb
Taylor, Richard D.
141004d4-95a6-44f1-93ce-ca36c1b34d61
Bruce Macdonald, Hannah
8e3f96bf-6806-4dc9-bd25-5b7a5325c7a7
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5

Samways, Marley, Luke, Taylor, Richard D., Bruce Macdonald, Hannah and Essex, Jonathan W. (2021) Water molecules at protein-drug interfaces: computational prediction and analysis methods. Chemical Society Reviews, 50 (16), 9104-9120. (doi:10.1039/D0CS00151A).

Record type: Article

Abstract

The fundamental importance of water molecules at drug-protein interfaces is now widely recognised and a significant feature in structure-based drug design. Experimental methods for analysing the role of water in drug binding have many challenges, including the accurate location of bound water molecules in crystal structures, and problems in resolving specific water contributions to binding thermodynamics. Computational analyses of binding site water molecules provide an alternative, and in principle complete, structural and thermodynamic picture, and their use is now commonplace in the pharmaceutical industry. In this review, we describe the computational methodologies that are available and discuss their strengths and weaknesses. Additionally, we provide a critical analysis of the experimental data used to validate the methods, regarding the type and quality of experimental structural data. We also discuss some of the fundamental difficulties of each method and suggest directions for future study.

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water-review - Accepted Manuscript
Restricted to Repository staff only until 29 June 2022.
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More information

Accepted/In Press date: 29 June 2021
e-pub ahead of print date: 29 June 2021
Published date: 21 August 2021
Additional Information: Funding Information: The authors thank the EPSRC for funding. MLS is supported by the EPSRC-funded CDT in Next Generation Computational Modelling, under grant EP/L015382/1. HEBM was supported by the EPSRC-funded CDT in Theory and Modelling in Chemical Sciences, under grant EP/L015722/1 during this work. The authors thank Dr Philip Williamson (Biological Sciences, University of Southampton) for helpful discussions regarding the use of NMR in this field. Funding Information: RDT is an employee of UCB, and research conducted by MLS, HEBM and JWE has been partly funded by UCB. HEBM is an employee of MSD.

Identifiers

Local EPrints ID: 451264
URI: http://eprints.soton.ac.uk/id/eprint/451264
ISSN: 0306-0012
PURE UUID: e11cb29b-97d1-488d-b174-08762b016c03
ORCID for Marley, Luke Samways: ORCID iD orcid.org/0000-0001-9431-8789
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 15 Sep 2021 16:31
Last modified: 26 Nov 2021 03:12

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Contributors

Author: Marley, Luke Samways ORCID iD
Author: Richard D. Taylor
Author: Hannah Bruce Macdonald

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