Multiscale computational analysis reveals enhanced allosteric modulation of Nav1.5 by dual binding of dapagliflozin and ertugliflozin

Figures

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  Fig. 1. Structural difference between dapagliflozin and ertugliflozin. The extra methyl group and oxygen atom in ertugliflozin shown in red circle.

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  Fig. 2. (A) Representative late INa recorded before and after application of dapagliflozin. (B) Representative late INa recorded before and after application of ertugliflozin. (C) A quantitative comparison shows that dapagliflozin inhibits late INa with higher potency and efficacy than ertugliflozin, while neither drug affects the peak current.

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  Fig. 3. (A) The top view of our predicted full structure of Nav1.5-Dapagliflozin in both binding sites; Each domain is colored in different colours. DI: red, DII: yellow, DIII: green, DIV: blue, DIII-DIV loop: orange, Rest of the protein(loops): silver. (B) Side view of our docked Nav1.5-Dapagliflozin in both binding site structures with membrane and water. We used VMD for MACOSXX86_64, version 1.9.4a57 (http://www.ks.uiuc.edu/Research/vmd/) to generate these figures.

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  Fig. 4. (A) Average RMSD and (B) Average B-factor of all systems from all replicas.

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  Fig. 5. Mutational sites in BS1 and BS2, while two dapagliflozin ligands are docked in both sites. The yellow colour denotes the original amino acids, and the blue colour indicates the amino acids after mutation. We used VMD for MACOSXX86_64, version 1.9.4a57 (http://www.ks.uiuc.edu/Research/vmd/) to generate this figure.

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  Fig. 6. A. Nav1.5-dapagliflozin compound. Yellow-colored residues were found to form strong hydrogen bonds with the ligand, characterized by distances of less than ~ 3.5 Å. Black dots represent inter-ligand hydrogen bonds. Purple residues exhibit a high binding affinity with the ligands. B. Binding pocket between Nav1.5 and dapagliflozin in BS1 and BS2. (C) Mode of binding between Nav1.5-ertugliflozin compound in dual ligand case. (D) Binding pocket between Nav1.5 and ertugliflozin in BS1 and BS2. . We used VMD for MACOSXX86_64, version 1.9.4a57 (http://www.ks.uiuc.edu/Research/vmd/) to generate these figures.

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  Fig. 7. (A) SASA analysis of Nav-dapagliflozin and Nav-ertugliflozin complex in dual binding site configuration. (B) RDF analysis of Nav-dapagliflozin and Nav-ertugliflozin complex in dual binding site configuration.

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  Fig. 8. (A) Statistical significance of DIII-IV loop(Resid: 1471–1523) based on B-factor values when ertugliflozin docked in both sites in Nav1.5. The overlap between the two lines means no statistical significance. (B) DIII-DIV loop when dapagliflozin is docked in both sites in Nav1.5. (C) Statistical significance residues in the Nav1.5-dapagliflozin complex in yellow. (D) Statistical significance residues in Nav1.5-ertugliflozin complex in red. We used VMD for MACOSXX86_64, version 1.9.4a57 (http://www.ks.uiuc.edu/Research/vmd/) to generate the Fig. 8C and D.

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  Fig. 9. Comparison of PCA analysis of All atomistic model (blue) vs. CG model (red).

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  Fig. 10. Correlation Matrix of Nav-dapa & Nav-ertu complex focusing KHBPs in dual occupancy scenario after 200ns. (A, B). Correlation Matrix of Nav-dapa & Nav-ertu complex focusing KHBPs in dual occupancy scenario after 3 microseconds (C, D). The average distance between KHBPs after 200 ns and 3 microseconds in different scenario. (E, F).