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Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo
Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo
Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.
Aldeghi, Matteo
13796b74-63d0-4d31-a5f4-06fb25b28a14
Ross, Gregory A
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Bodkin, Michael J.
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Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Knapp, Stefan
daf5db97-4fad-469f-b531-10b5bdc81ac5
Biggin, Philip C.
c7394f79-450a-46c6-b77a-fadac30ded33
Aldeghi, Matteo
13796b74-63d0-4d31-a5f4-06fb25b28a14
Ross, Gregory A
113a6add-41b2-4ccc-9ab9-73fb52d728c5
Bodkin, Michael J.
0bfd655c-9764-4e50-9a46-02e24937aaa6
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Knapp, Stefan
daf5db97-4fad-469f-b531-10b5bdc81ac5
Biggin, Philip C.
c7394f79-450a-46c6-b77a-fadac30ded33

Aldeghi, Matteo, Ross, Gregory A, Bodkin, Michael J., Essex, Jonathan W., Knapp, Stefan and Biggin, Philip C. (2018) Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo. Communications Chemistry, 1. (doi:10.1038/s42004-018-0019-x).

Record type: Article

Abstract

Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.

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More information

Accepted/In Press date: 1 March 2018
e-pub ahead of print date: 5 April 2018
Published date: 5 April 2018

Identifiers

Local EPrints ID: 420728
URI: https://eprints.soton.ac.uk/id/eprint/420728
PURE UUID: b827fba1-29c0-4021-978b-e8b1f71061f3
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 14 May 2018 16:30
Last modified: 14 Mar 2019 01:52

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