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In silico drug repurposing at the cytoplasmic surface of human aquaporin 1

ALED LLOYD, Karl Austin-Muttitt, Jonathan Mullins Orcid Logo

PLOS ONE, Volume: 20, Issue: 1, Start page: e0314151

Swansea University Authors: ALED LLOYD, Karl Austin-Muttitt, Jonathan Mullins Orcid Logo

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DOI (Published version): 10.1371/journal.pone.0314151

Abstract

Aquaporin 1 (AQP1) is a key channel for water transport in peritoneal dialysis. Inhibition of AQP1 could therefore impair water transport during peritoneal dialysis. It is not known whether inhibition of AQP1 occurs unintentionally due to off-target interactions of administered medications. A high-t...

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ISSN: 1932-6203
Published: Public Library of Science (PLoS) 2025
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spelling 2025-02-17T11:10:18.4569078 v2 68767 2025-01-30 In silico drug repurposing at the cytoplasmic surface of human aquaporin 1 139ecfe3c4c3c3d92aa7f87612bffd90 ALED LLOYD ALED LLOYD true true fafc0917b48af4eaec154646854867f8 Karl Austin-Muttitt Karl Austin-Muttitt true false 4cf2dddedbe1dacb506ec925fdbd5b40 0000-0003-0144-2962 Jonathan Mullins Jonathan Mullins true false 2025-01-30 Aquaporin 1 (AQP1) is a key channel for water transport in peritoneal dialysis. Inhibition of AQP1 could therefore impair water transport during peritoneal dialysis. It is not known whether inhibition of AQP1 occurs unintentionally due to off-target interactions of administered medications. A high-throughput virtual screening study has been performed to investigate the possible binding of licensed medications to the water pore of human AQP1. A complete model of human AQP1 based on its canonical sequence was assembled using I-TASSER and MODELLER. The model was refined via the incorporation of pore water molecules from a high-resolution yeast aquaporin structure. Docking studies were conducted for the cytoplasmic domain of the AQP1 monomer against a library of all compounds listed in the British National Formulary (BNF), using the PLANTS software with the ChemPLP scoring function. The stability of the best docked conformations within the intrinsic water pore was assessed via short 15 nanosecond molecular dynamics (MD) simulations using the GROMACS-on-Colab utility. Of the 1512 compounds tested, 1002 docking results were obtained, and 198 of these conformations occupied a position within the intrinsic water pore. 30 compounds with promising docking scores were assessed by MD. The docked conformations for dopamine, gabapentin, pregabalin, and methyldopa were stable in these short MD studies. For furosemide and pravastatin, the MD trajectory suggested a binding mode different to the docking result. A small set of compounds which could impede water transport through human AQP1 have been identified in this computational screening study. Journal Article PLOS ONE 20 1 e0314151 Public Library of Science (PLoS) 1932-6203 Hydrogen bonding , Drug interactions , Molecular dynamics , Dopamine , Molecular structure, Monomers , Protein structure, Transport inhibition assay 9 1 2025 2025-01-09 10.1371/journal.pone.0314151 COLLEGE NANME COLLEGE CODE Swansea University SU Library paid the OA fee (TA Institutional Deal) Swansea University 2025-02-17T11:10:18.4569078 2025-01-30T17:28:52.8219546 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine ALED LLOYD 1 Karl Austin-Muttitt 2 Jonathan Mullins 0000-0003-0144-2962 3 68767__33599__5cfdfc1f747a4dce93e137429c673ace.pdf 68767.VOR.pdf 2025-02-17T10:44:41.9522013 Output 2049522 application/pdf Version of Record true © 2025 Lloyd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0). true eng http://creativecommons.org/licenses/by/4.0/
title In silico drug repurposing at the cytoplasmic surface of human aquaporin 1
spellingShingle In silico drug repurposing at the cytoplasmic surface of human aquaporin 1
ALED LLOYD
Karl Austin-Muttitt
Jonathan Mullins
title_short In silico drug repurposing at the cytoplasmic surface of human aquaporin 1
title_full In silico drug repurposing at the cytoplasmic surface of human aquaporin 1
title_fullStr In silico drug repurposing at the cytoplasmic surface of human aquaporin 1
title_full_unstemmed In silico drug repurposing at the cytoplasmic surface of human aquaporin 1
title_sort In silico drug repurposing at the cytoplasmic surface of human aquaporin 1
author_id_str_mv 139ecfe3c4c3c3d92aa7f87612bffd90
fafc0917b48af4eaec154646854867f8
4cf2dddedbe1dacb506ec925fdbd5b40
author_id_fullname_str_mv 139ecfe3c4c3c3d92aa7f87612bffd90_***_ALED LLOYD
fafc0917b48af4eaec154646854867f8_***_Karl Austin-Muttitt
4cf2dddedbe1dacb506ec925fdbd5b40_***_Jonathan Mullins
author ALED LLOYD
Karl Austin-Muttitt
Jonathan Mullins
author2 ALED LLOYD
Karl Austin-Muttitt
Jonathan Mullins
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publishDate 2025
institution Swansea University
issn 1932-6203
doi_str_mv 10.1371/journal.pone.0314151
publisher Public Library of Science (PLoS)
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Aquaporin 1 (AQP1) is a key channel for water transport in peritoneal dialysis. Inhibition of AQP1 could therefore impair water transport during peritoneal dialysis. It is not known whether inhibition of AQP1 occurs unintentionally due to off-target interactions of administered medications. A high-throughput virtual screening study has been performed to investigate the possible binding of licensed medications to the water pore of human AQP1. A complete model of human AQP1 based on its canonical sequence was assembled using I-TASSER and MODELLER. The model was refined via the incorporation of pore water molecules from a high-resolution yeast aquaporin structure. Docking studies were conducted for the cytoplasmic domain of the AQP1 monomer against a library of all compounds listed in the British National Formulary (BNF), using the PLANTS software with the ChemPLP scoring function. The stability of the best docked conformations within the intrinsic water pore was assessed via short 15 nanosecond molecular dynamics (MD) simulations using the GROMACS-on-Colab utility. Of the 1512 compounds tested, 1002 docking results were obtained, and 198 of these conformations occupied a position within the intrinsic water pore. 30 compounds with promising docking scores were assessed by MD. The docked conformations for dopamine, gabapentin, pregabalin, and methyldopa were stable in these short MD studies. For furosemide and pravastatin, the MD trajectory suggested a binding mode different to the docking result. A small set of compounds which could impede water transport through human AQP1 have been identified in this computational screening study.
published_date 2025-01-09T05:26:23Z
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