Computational structural studies of SGLT2-related polypharmacy

LLOYD, ALED; Austin-Muttitt, Karl; Mullins, Jonathan

doi:10.1371/journal.pone.0334656

Journal article 278 views 39 downloads

Computational structural studies of SGLT2-related polypharmacy

ALED LLOYD, Karl Austin-Muttitt, Jonathan Mullins

PLOS One, Volume: 20, Issue: 10, Start page: e0334656

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

PDF | Version of Record

© 2025 Lloyd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY).
Download (1.06MB)

Check full text

DOI (Published version): 10.1371/journal.pone.0334656

Abstract

Introduction: Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients...

Full description

Published in:	PLOS One
ISSN:	1932-6203
Published:	Public Library of Science (PLoS) 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa70738

first_indexed	2025-10-20T14:46:41Z
last_indexed	2025-11-12T08:16:31Z
id	cronfa70738
recordtype	SURis
fullrecord	<?xml version="1.0"?><rfc1807><datestamp>2025-11-11T09:40:29.1809471</datestamp><bib-version>v2</bib-version><id>70738</id><entry>2025-10-20</entry><title>Computational structural studies of SGLT2-related polypharmacy</title><swanseaauthors><author><sid>139ecfe3c4c3c3d92aa7f87612bffd90</sid><firstname>ALED</firstname><surname>LLOYD</surname><name>ALED LLOYD</name><active>true</active><ethesisStudent>true</ethesisStudent></author><author><sid>fafc0917b48af4eaec154646854867f8</sid><firstname>Karl</firstname><surname>Austin-Muttitt</surname><name>Karl Austin-Muttitt</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>4cf2dddedbe1dacb506ec925fdbd5b40</sid><ORCID>0000-0003-0144-2962</ORCID><firstname>Jonathan</firstname><surname>Mullins</surname><name>Jonathan Mullins</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2025-10-20</date><abstract>Introduction: Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients are prescribed these compounds, raising questions about polypharmacy. We have performed a computational drug repurposing screen to identify other licensed drugs capable of binding at or near the SGLT2i active site aiming to identify compounds that could either compete with SGLT2i or inhibit sodium and glucose transport. Methods: The library of BNF listed compounds was obtained from NCBI PubChem. D-I-TASSER was used to generate monomeric structural models, and MODELLER was used to incorporate MAP-17 and empagliflozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The structural model was refined in a 5 nanosecond GROMACS equilibration. Docking studies using PLANTS were performed and compounds interacting with key protein residues were identified. CHARM-GUI was used to prepare membrane- and ligand-bound systems to run in GROMACS using GPUs in Google Colab. 10 nanosecond simulations were undertaken (300 Kelvin and 1 bar) to discriminate between binding and non-binding events. Results: The SGLT2-MAP17 structure was obtained in the inward-open conformation, showing good agreement with published structures. Existing SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) all feature in the top 1% of docked compounds in the repurposing screen. 17 compounds were investigated by MD, with all of them remaining bound to the protein in simulation. Ceftriaxone, tobramycin, clindamycin, fluvastatin, atorvastatin and ticagrelor were among the compounds with potentially significant interactions. Discussion: It is not clear whether the stable ligand interactions identified here would result in inhibition of sodium and glucose transport, or if the interactions could provide competitive inhibition for SGLT2i compounds currently used. The compounds identified are not presently recognised as interacting with SGLT2i, nor are they associated with any adverse effects suggesting inhibition of the protein. This study is limited by considering only the protein-ligand interaction and not wider pharmacokinetic or pharmacodynamic factors. Conclusion: The indication of interactions with several compounds likely to be prescribed alongside SGLT2 inhibitors, such as antibiotics, statins, and antiplatelet agents, warrants further investigation of the potential for polypharmacological complications.</abstract><type>Journal Article</type><journal>PLOS One</journal><volume>20</volume><journalNumber>10</journalNumber><paginationStart>e0334656</paginationStart><paginationEnd/><publisher>Public Library of Science (PLoS)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>1932-6203</issnElectronic><keywords/><publishedDay>17</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-10-17</publishedDate><doi>10.1371/journal.pone.0334656</doi><url/><notes/><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><apcterm>SU Library paid the OA fee (TA Institutional Deal)</apcterm><funders>Swansea University</funders><projectreference/><lastEdited>2025-11-11T09:40:29.1809471</lastEdited><Created>2025-10-20T15:41:23.5206804</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>ALED</firstname><surname>LLOYD</surname><order>1</order></author><author><firstname>Karl</firstname><surname>Austin-Muttitt</surname><order>2</order></author><author><firstname>Jonathan</firstname><surname>Mullins</surname><orcid>0000-0003-0144-2962</orcid><order>3</order></author></authors><documents><document><filename>70738__35417__b4177f91746e425297e34e664b65ab44.pdf</filename><originalFilename>pone.0334656.pdf</originalFilename><uploaded>2025-10-20T15:41:23.5205568</uploaded><type>Output</type><contentLength>1115050</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2025 Lloyd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY).</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>http://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling	2025-11-11T09:40:29.1809471 v2 70738 2025-10-20 Computational structural studies of SGLT2-related polypharmacy 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 2025-10-20 Introduction: Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients are prescribed these compounds, raising questions about polypharmacy. We have performed a computational drug repurposing screen to identify other licensed drugs capable of binding at or near the SGLT2i active site aiming to identify compounds that could either compete with SGLT2i or inhibit sodium and glucose transport. Methods: The library of BNF listed compounds was obtained from NCBI PubChem. D-I-TASSER was used to generate monomeric structural models, and MODELLER was used to incorporate MAP-17 and empagliflozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The structural model was refined in a 5 nanosecond GROMACS equilibration. Docking studies using PLANTS were performed and compounds interacting with key protein residues were identified. CHARM-GUI was used to prepare membrane- and ligand-bound systems to run in GROMACS using GPUs in Google Colab. 10 nanosecond simulations were undertaken (300 Kelvin and 1 bar) to discriminate between binding and non-binding events. Results: The SGLT2-MAP17 structure was obtained in the inward-open conformation, showing good agreement with published structures. Existing SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) all feature in the top 1% of docked compounds in the repurposing screen. 17 compounds were investigated by MD, with all of them remaining bound to the protein in simulation. Ceftriaxone, tobramycin, clindamycin, fluvastatin, atorvastatin and ticagrelor were among the compounds with potentially significant interactions. Discussion: It is not clear whether the stable ligand interactions identified here would result in inhibition of sodium and glucose transport, or if the interactions could provide competitive inhibition for SGLT2i compounds currently used. The compounds identified are not presently recognised as interacting with SGLT2i, nor are they associated with any adverse effects suggesting inhibition of the protein. This study is limited by considering only the protein-ligand interaction and not wider pharmacokinetic or pharmacodynamic factors. Conclusion: The indication of interactions with several compounds likely to be prescribed alongside SGLT2 inhibitors, such as antibiotics, statins, and antiplatelet agents, warrants further investigation of the potential for polypharmacological complications. Journal Article PLOS One 20 10 e0334656 Public Library of Science (PLoS) 1932-6203 17 10 2025 2025-10-17 10.1371/journal.pone.0334656 COLLEGE NANME COLLEGE CODE Swansea University SU Library paid the OA fee (TA Institutional Deal) Swansea University 2025-11-11T09:40:29.1809471 2025-10-20T15:41:23.5206804 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science ALED LLOYD 1 Karl Austin-Muttitt 2 Jonathan Mullins 0000-0003-0144-2962 3 70738__35417__b4177f91746e425297e34e664b65ab44.pdf pone.0334656.pdf 2025-10-20T15:41:23.5205568 Output 1115050 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). true eng http://creativecommons.org/licenses/by/4.0/
title	Computational structural studies of SGLT2-related polypharmacy
spellingShingle	Computational structural studies of SGLT2-related polypharmacy ALED LLOYD Karl Austin-Muttitt Jonathan Mullins
title_short	Computational structural studies of SGLT2-related polypharmacy
title_full	Computational structural studies of SGLT2-related polypharmacy
title_fullStr	Computational structural studies of SGLT2-related polypharmacy
title_full_unstemmed	Computational structural studies of SGLT2-related polypharmacy
title_sort	Computational structural studies of SGLT2-related polypharmacy
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
format	Journal article
container_title	PLOS One
container_volume	20
container_issue	10
container_start_page	e0334656
publishDate	2025
institution	Swansea University
issn	1932-6203
doi_str_mv	10.1371/journal.pone.0334656
publisher	Public Library of Science (PLoS)
college_str	Faculty of Medicine, Health and Life Sciences
hierarchytype
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 - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str	1
active_str	0
description	Introduction: Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients are prescribed these compounds, raising questions about polypharmacy. We have performed a computational drug repurposing screen to identify other licensed drugs capable of binding at or near the SGLT2i active site aiming to identify compounds that could either compete with SGLT2i or inhibit sodium and glucose transport. Methods: The library of BNF listed compounds was obtained from NCBI PubChem. D-I-TASSER was used to generate monomeric structural models, and MODELLER was used to incorporate MAP-17 and empagliflozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The structural model was refined in a 5 nanosecond GROMACS equilibration. Docking studies using PLANTS were performed and compounds interacting with key protein residues were identified. CHARM-GUI was used to prepare membrane- and ligand-bound systems to run in GROMACS using GPUs in Google Colab. 10 nanosecond simulations were undertaken (300 Kelvin and 1 bar) to discriminate between binding and non-binding events. Results: The SGLT2-MAP17 structure was obtained in the inward-open conformation, showing good agreement with published structures. Existing SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) all feature in the top 1% of docked compounds in the repurposing screen. 17 compounds were investigated by MD, with all of them remaining bound to the protein in simulation. Ceftriaxone, tobramycin, clindamycin, fluvastatin, atorvastatin and ticagrelor were among the compounds with potentially significant interactions. Discussion: It is not clear whether the stable ligand interactions identified here would result in inhibition of sodium and glucose transport, or if the interactions could provide competitive inhibition for SGLT2i compounds currently used. The compounds identified are not presently recognised as interacting with SGLT2i, nor are they associated with any adverse effects suggesting inhibition of the protein. This study is limited by considering only the protein-ligand interaction and not wider pharmacokinetic or pharmacodynamic factors. Conclusion: The indication of interactions with several compounds likely to be prescribed alongside SGLT2 inhibitors, such as antibiotics, statins, and antiplatelet agents, warrants further investigation of the potential for polypharmacological complications.
published_date	2025-10-17T05:28:03Z
_version_	1851550842441695232
score	11.089988

Computational structural studies of SGLT2-related polypharmacy

Similar Items