Molecular Ion Channel Blockers of Influenza A and SARS-CoV-2 Viruses

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Abstract

Drug molecules that block the functional cycle of influenza A and SARS-CoV-2 viruses are proposed. The blocker molecules effectively binding inside the M2 and E-channels of influenza A and SARS-CoV-2 viruses and blocking the diffusion of H+/K+ ions destroy the functional cycle of viruses. A family of positively charged, +2 e. u., molecular blockers of H+ /K+ ion diffusion through M2 and E-channels is proposed. The blocker molecules, derivatives of diazabicyclooctane, was investigated for its binding affinity to the channels M2 and E. Thermal dynamics and binding affinity were modeled by the exhaustive docking method sites. Blocker molecules with higher affinity for the blocking sites were proposed. The most probable mutations of amino acids of protein M2 and E channels are considered, the effectiveness of channel blocking are analyzed and optimal structures of blocker molecules are proposed.

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About the authors

Yu. N. Vorobjev

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch Russia Academy of Sciences

Author for correspondence.
Email: ynvorob@niboch.nsc.ru
Russian Federation, Novosibirsk, 630090

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Supplementary files

Supplementary Files
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2. Fig. 1. Structure of molecules of E- and M2-channel blockers. a – DABCO; b – DABCOB; c – DABCO3B; g – DABCON; d – DABCO3N.

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3. Fig. 2. Ionized HIS+ fraction of histidine residues (a) and fraction of neutral tautomer HIE (b). His37A (black), His37B (red), His37C (blue), HIS37D (green), protein M2 at pH 6.5, T = 300 K, along the equilibrium MD trajectory in 25 ns.

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4. Fig. 3. The main binding site of DABCOB molecules with the native M2 channel.

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5. Fig. 4. Fluctuations of potential energy of native and mutant structures of the E-channel at T= 308K, pH 6.5; black – native structure, red – mut1, green – mut2.

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6. Fig. 5. Structure of the most probable, highest binding energy, complexes of the native E-channel with optimally bound blocker molecules: DABCO (a); DABCOB (b); DABCO3B (c); DABCON (d); DABCO3N (d).

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7. Fig. 6. Structure of the most probable complexes of the mutant, mut1, E-channel with optimally bound blocker molecules: DABCO (a), DABCOB (b), DABCO3B (c), DABCON (d), DABCO3N (d).

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8. Fig. 7. Structure of the most probable complexes of the E channel mutant, mut2, with blocker molecules: (a) DABCO; (b) DABCOB; (c) DABCO3B; (d) DABCON; (d) DABCO3N.

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