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PreprintCited by 2Cardiac electrophysiology and arrhythmiasIon channel regulation and functionProtein Structure and Dynamics

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Multiscale Computational Analysis of Nav1.5 Modulation by SGLT2 Inhibitors Dapagliflozin and Ertugliflozin: Dual Binding Enhances Allosteric Effects over Single Occupancy

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Chattopadhyay, Arkapravo, Fatehi, Mohammad, Mosa, Farag E.S., Gruber, Brittany, Light, Peter E., Barakat, Khaled·2025·Scientific Reports
DOI 10.21203/rs.3.rs-7602999/v1PMC PMC12780251

Preprint — published as 10.1038/s41598-025-30298-6 · Paper page

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Abstract

The cardiac sodium channel (Nav1.5) serves as a crucial regulator of cardiac excitability and presents a potential therapeutic target. While the SGLT2 inhibitor dapagliflozin has exhibited cardioprotective effects, its structurally similar counterpart, ertugliflozin, which differs solely by an additional oxygen and methyl group, does not confer cardio-protection. To examine this discrepancy, a multiscale computational approach combining all-atom molecular dynamics (MD) and coarse-grained (CG) simulations was employed to analyze ligand interactions with Nav1.5 in both single and dual-binding site configurations. All-atom simulations revealed localized residue fluctuations but were inadequate for capturing system-wide allosteric effects. Consequently, CG models were derived from atomistic trajectories to improve conformational sampling. Critical residues regulating binding sites were identified through B-factor analyses in three replicas of all-atom models. Harmonic restraints were subsequently applied to these residues within the CG models to simulate ligand-induced rigidity. Notably, in the dual-binding configurations, ertugliflozin’s additional oxygen established a hydrogen bond interaction with Y1767, a mutation site associated with pathological late I Na . This interaction was absent in single-site configurations and may elucidate the functional divergence between the two compounds. Furthermore, inter-residue distances between the IFMT motif, involving domains III and IV related to channel gating, were monitored to assess inactivation states across the various systems. This investigation underscores how dual-site occupancy and subtle chemical differences in ligands can impact Nav1.5 dynamics. The findings provide a foundation for structure-based design of selective modulators targeting sodium channels via allosteric mechanisms.

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Metadata

Authors
Chattopadhyay, A., Fatehi, M., Mosa, F. E. S., Gruber, B., Light, P. E., & Barakat, K.
Affiliations
University of Alberta (CA)
Corresponding author
Barakat, Khaled
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2025-10-06
Volume
16
Issue
1
Pages
741-741
ISSN
2045-2322 (ISSN-L)
DOI
10.21203/rs.3.rs-7602999/v1
PMC
PMC12780251
OpenAlex
W4416895284
Cited by
2
References
1
Citations by year
2026: 2
FWCI
1.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Alliance de recherche numérique du Canada
  • Canadian Institutes of Health Research (183967_1)
  • Natural Sciences and Engineering Research Council of Canada (RGPIN 2020, rgpin-2020-04437)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
cardiac sodium channel, allosteric modulation, dapagliflozin, ertugliflozin, SGLT2 inhibitors, late sodium current, channel inactivation, coarse-grained models, B-factor analysis, ligand binding, structure-based drug design
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Allosteric Regulation, Benzhydryl Compounds, Binding Sites, Glucosides, Humans, Ligands, Protein Binding, Bridged Bicyclo Compounds, Heterocyclic, Molecular Dynamics Simulation, NAV1.5 Voltage-Gated Sodium Channel

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