In Silico Analysis Revealed a Unique Binding but Ineffective Mode of Amantadine to Influenza Virus B M2 Channel
Yue Zhang1, Qing-Chuan Zheng1,2
1Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, International Joint Research Laboratory of Nano-Micro Architecture Chemistry, College of Chemistry, Jilin University, Changchun 130023, People's Republic of China.
Abstract:
The M2 proton channel of influenza A (AM2) and B (BM2) have a highly conserved function motif, considered as the effective target. As yet, there is no effective drug against BM2. Research showed that AM2 channel blocker, amantadine (AMT), was able to bind to BM2 channel, but AMT lacked inhibition against BM2. Nevertheless, the study of the binding but ineffective mode of AMT to BM2 is challenging. To resolve the challenge and obtain more information for drug design of inhibitors targeting BM2, multiple molecular dynamics simulations were performed. We discovered AMT mainly adopted up binding mode in BM2, involved in a transition flipping from down mode to up mode. Furthermore, we discovered a new key factor to explain ineffective inhibition of AMT to BM2 because of the unmatched spatial geometry between AMT and BM2. Our work could enrich structural feature information on BM2 and provide a new perspective for rational drug design of anti-influenza B.
Insights
Amantadine binds to the influenza B virus M2 channel but doesn't inhibit it. Molecular dynamics reveal an "up" binding mode and spatial geometry mismatch, crucial for designing new anti-influenza B drugs.
Area of Science:
- Biophysics
- Structural Biology
- Virology
Background:
- Influenza A (AM2) and B (BM2) viruses possess conserved M2 proton channels, potential drug targets.
- No effective drugs currently exist against BM2, posing a public health challenge.
Purpose of the Study:
- Investigate the binding mechanism of amantadine (AMT) to the BM2 channel.
- Elucidate the reasons for AMT's lack of inhibition against BM2.
- Provide insights for rational drug design of novel anti-influenza B agents.
Main Methods:
- Multiple molecular dynamics simulations were employed.
- Analysis of amantadine's binding modes within the BM2 channel.
Main Results:
- Amantadine (AMT) primarily adopts an "up" binding mode in the BM2 channel, transitioning from a "down" mode.
- A key factor identified for AMT's ineffective inhibition is the spatial geometry mismatch between AMT and BM2.
Conclusions:
- The study enriches the structural understanding of the BM2 channel.
- Findings offer a new perspective for developing effective BM2 inhibitors against influenza B infections.
