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Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling
School of Biotechnology, Ho Chi Minh International University, Quarter 6, Linh Trung, Thu Duc District, Ho Chi Minh City 70000, Vietnam
Pharmaceutical Design and Simulation (PhDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Minden, Pulau Pinang, Malaysia
* Authors to whom correspondence should be addressed.
Received: 6 September 2011; in revised form: 6 December 2011 / Accepted: 8 December 2011 / Published: 8 December 2011
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.
Keywords: M2 channel inhibitors; adamantane-based drugs; virtual screening; pharmacophore modeling
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Tran, L.; Choi, S.B.; Al-Najjar, B.O.; Yusuf, M.; Wahab, H.A.; Le, L. Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling. Molecules 2011, 16, 10227-10255.
Tran L, Choi SB, Al-Najjar BO, Yusuf M, Wahab HA, Le L. Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling. Molecules. 2011; 16(12):10227-10255.
Tran, Linh; Choi, Sy Bing; Al-Najjar, Belal O.; Yusuf, Muhammad; Wahab, Habibah A.; Le, Ly. 2011. "Discovery of Potential M2 Channel Inhibitors Based on the Amantadine Scaffold via Virtual Screening and Pharmacophore Modeling." Molecules 16, no. 12: 10227-10255.