In silico Exploration of Interactions Between Potential COVID-19 Antiviral Treatments and the Pore of the hERG Potassium Channel—A Drug Antitarget

Figures

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  Figure 1. Location of the assigned binding site of atazanavir in the hERG cryo-EM structure and the closely related Dickson et al. model with the drug docked in the configuration shown in the methods section. The complete structure in (A) and (B) illustrates the location of segment 6 (S6) lining the pore where key residues such as Y652 and F656 are located and the outer S5 segment where F557, a major residue of the side pocket, is located. The selectivity filter region (SF) is also annotated where T623 and S624 sit at the base of the pore helix attached to it. Atazanavir is represented as a space-filling structure in which carbon atoms are represented in yellow, nitrogen in blue, oxygen in red. Major amino acid constituents of the binding sites were shown as sticks. In all structure figures, the hERG pore amino acid side chains are colored as follows: Phe-557, gray; Thr-623 and Ser-624, green; Tyr-652, pink; and Phe-656, blue. Atazanavir is shown in yellow. (A,B) show low-energy-score pose for atazanavir docked into the hERG pore with docking biased to promote occupation of canonical binding site. Annotations (dotted lines) define potential interactions between drug and amino acid side…

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  Figure 2. Location of the assigned pore binding site of lopinavir in the hERG cryo-EM structure and the closely related Dickson et al. model with the drug docked in the configuration shown in the methods section. The complete structure in (A,B) shows the location of segment 6 (S6) lining the pore where key residues such as Y652 and F656 are located and the outer S5 segment where F557, a major residue of the side pocket, is located. The selectivity SF was also annotated where T623 and S624 sit at the base of the pore helix attached to it. Lopinavir is represented as a space-filling structure. Major amino acid constituents of the binding sites were shown as sticks. Binding residues and atoms of the drug molecule colored as for Figure 1. (A,B) show low-energy-score pose for lopinavir docked into the hERG pore with docking biased to promote occupation of the canonical binding site. (A) shows the lopinavir docking in the hERG cryo-EM structure. (B) shows the lopinavir docking in the Dickson et al. model based on hERG cryo-EM structure. Annotations (dotted lines) define potential interactions between drug and amino acid side chains, distances in (A) between the drug molecule and key residues…

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  Figure 3. Location of the assigned pore binding site of ritonavir in the hERG cryo-EM structure and the closely related Dickson et al. model with the drug docked in the configuration shown in the methods section. The complete structure in (A,B) shows the location of segment 6 (S6) lining the pore where key residues such as Y652 and F656 are located and the outer S5 segment where F557, a major residue of the side pocket, is located. The selectivity SF was also annotated where T623 and S624 sit at the base of the pore helix attached to it. Ritonavir is represented as a space-filling yellow surface. Major amino acid constituents of the binding sites were shown as sticks in the box. Binding residues and atoms of drug molecule colored as for Figure 1. (A,B) show low-energy-score pose for ritonavir docked into the hERG pore with docking biased to promote occupation of canonical binding site. Annotations (dotted lines) define potential interactions between drug and amino acid side chains, distances in (A) between the drug molecule and key residues were written adjacent to each dotted line. (A) Shows the ritonavir docking in the hERG cryo-EM structure. B Shows the ritonavir docking in the Dickson…

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  Figure 4. Location of the assigned pore binding site of remdesivir in the hERG cryo-EM structure and the closely related Dickson et al. model and the house MD model with the drug docked in the configuration shown in the methods section. The complete structure in (A) shows the location of segment 6 (S6) lining the pore where key residues such as Y652 and F656 are located and the outer S5 segment where F557, a major residue of the side pocket, is located. The selectivity SF was also annotated where T623 and S624 sit at the base of the pore helix attached to it. Remdesivir is represented as a space-filling yellow surface. Major amino acid constituents of the binding sites were shown as sticks. Binding residues and atoms of drug molecule colored as for Figure 1. (A,B) show low-energy-score pose for remdesivir docked into the hERG pore with docking biased to promote occupation of canonical binding site. Annotations (dotted lines) define potential interactions between drug and amino acid side chains, distances in A between the drug molecule and key residues were written adjacent to each dotted line. (C) shows the low-energy-score pose for remdesivir docked into the hERG pore with docking biased…

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  Figure 5. Location of the assigned binding site of favipiravir in the hERG cryo-EM structure. The complete structure shows the location of segment 6 (S6) lining the pore where key residues such as Y652 and F656 are located and the outer S5 segment where F557, a major residue of the side pocket, is located. The selectivity SF was also annotated where T623 and S624 sit at the base of the pore helix attached to it. Favipiravir is represented as a space-filling surface. Major amino acid constituents of the binding sites were shown as sticks in the box. Binding residues and atoms of drug molecule colored as for Figure 1. The figure shows a low-energy-score pose for favipiravir docked into the hERG pore with docking biased to promote occupation of canonical binding site. Annotations (dotted lines) define potential interactions between drug and amino acid side chains, distances in A between the drug molecule and key residues were written adjacent to each dotted line.