Virtual screening and molecular growth guide the design of inhibitors for the influenza virus drug-resistant mutant M2-V27A/S31N

Abstract

The influenza A virus matrix protein 2 (AM2) protein is a proton-gated, proton-selective ion channel essential for influenza replication that has been identified as an antiviral target. The drug-resistance of the M2-V27A/S31N strain, which has been growing more prevalent in recent years and has the potential to spread globally, prevents current amantadine inhibitors from having the desired impact. In this study, we compiled the most common influenza A virus strains from 2001–2020 from the U.S. National Center for Biotechnology Information database and hypothesized that M2-V27A/S31N would become a common strain. The lead compound ZINC299830590 was screened for M2-V27A/S31N in the ZINC15 database using a pharmacophore model and molecular descriptors. This lead compound was then optimized by molecular growth, which allowed us to identify important amino acid residues and create interactions with them to produce compound 4. Molecular dynamics simulation showed that the complex of compound 4 and M2-V27A/S31N had certain degrees of stability and flexibility. The binding free energy of compound 4 was calculated using the MM/PB(GB)SA method and totaled −106.525 kcal/mol. Finally, physicochemical and pharmacokinetic profiles were predicted using the Absorption, Distribution, Metabolism, Excretion, and Toxicity model, which indicated the good bioavailability of compound 4. These results provide the basis for further in vivo and in vitro studies to demonstrate that compound 4 is a promising drug candidate against M2-V27A/S31N.

Communicated by Ramaswamy H. Sarma

Keywords:

• M2
• influenza virus
• drug resistance
• molecular growth
• molecular docking
• molecular dynamics
• virtual screening

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors gratefully acknowledge financial support from the Graduate Innovative Fund of the Graduate Innovative Fund of Wuhan Institute of Technology (No. CX2022025). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.