Abstract
Baloxavir marboxil (BXM), an antiviral drug for influenza virus, inhibits RNA replication by binding to RNA replication cap-dependent endonuclease (CEN) of influenza A and B viruses. Although this drug was only approved by the FDA in October 2018, drug resistant viruses have already been detected from clinical trials owing to an I38 mutation of CEN. To investigate the reduction of drug sensitivity by the I38 mutant variants, we performed a molecular dynamics (MD) simulation on the CEN-BXM complex structure to analyze variations in the mode of interaction. Our simulation results suggest that the side chain methyl group of I38 in CEN engages in a CH-pi interaction with the aromatic ring of BXM. This interaction is abolished in various I38 mutant variants. Moreover, MD simulation on various mutation models and binding free energy prediction by MM/GBSA method suggest that the I38 mutation precludes any interaction with the aromatic ring of BXA and thereby reduces BXA sensitivity.
Highlights
Influenza, a severe acute respiratory infection is estimated to affect 5 to 10% of adults and 20 to 30% of children[1]
Molecular dynamics (MD) simulations on the Cap-dependent Endonuclease (CEN)-baloxavir acid (BXA) complex model
MD simulations of CEN-BXA complex suggest that Tyr[24] and His[41] interact with BXA by pi-stacking and Glu[119] forms hydrogen bonds with BXA
Summary
A severe acute respiratory infection is estimated to affect 5 to 10% of adults and 20 to 30% of children[1]. Molecular dynamics (MD) simulation is used in drug discovery and optimization[23,24,25,26,27] This method considers the flexibility of the macromolecule based on Newtonian principles and can be applied to various biomolecules, such as protein, nucleic acid, and membranes[28,29,30,31]. MM/GBSA based on MD simulation results, is typically used to search for a new ligand or to optimize a ligand[33] This method can analyze the variation in the sensitivity of a ligand caused by mutations in amino acid residues of the protein[36]
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