title: Discovery of potential M2 channel inhibitors based on the amantadine scaffold via virtual screening and pharmacophore modeling.
abstract: The M2 channel protein on the influenza A virus membrane has become the main target of the anti-flu drugs amantadine and rimantadine. The structure of the M2 channel proteins of the H3N2 (PDB code 2RLF) and 2009-H1N1 (Genbank accession number GQ385383) viruses may help researchers to solve the drug-resistant problem of these two adamantane-based drugs and develop more powerful new drugs against influenza A virus. In the present study, we searched for new M2 channel inhibitors through a combination of different computational methodologies, including virtual screening with docking and pharmacophore modeling. Virtual screening was performed to calculate the free energies of binding between receptor M2 channel proteins and 200 new designed ligands. After that, pharmacophore analysis was used to identify the important M2  protein-inhibitor interactions and common features of top binding compounds with M2 channel proteins. Finally, the two most potential compounds were determined as novel leads to inhibit M2 channel proteins in both H3N2 and 2009-H1N1 influenza A virus.
authors.affiliation: School of Biotechnology, Ho Chi Minh International University, Quarter 6, Linh Trung, Thu Duc District, Ho Chi Minh City 70000, Vietnam.
authors.forename: Linh
authors.initials: L
authors.lastname: Tran
authors.forename: Sy Bing
authors.initials: SB
authors.lastname: Choi
authors.forename: Belal O
authors.initials: BO
authors.lastname: Al-Najjar
authors.forename: Muhammad
authors.initials: M
authors.lastname: Yusuf
authors.forename: Habibah A
authors.initials: HA
authors.lastname: Wahab
authors.forename: Ly
authors.initials: L
authors.lastname: Le
mesh_terms: D000547:Amantadine / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006860:Hydrogen Bonding / Q000187:drug effects; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000378:metabolism; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects / Q000378:metabolism; D049990:Membrane Transport Modulators / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D012299:Rimantadine / Q000737:chemistry; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D049990:Membrane Transport Modulators; D012299:Rimantadine; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins