Two Birds with One Stone ? Possible Dual-Targeting H 1 N 1 Inhibitors from Traditional Chinese Medicine

The H1N1 influenza pandemic of 2009 has claimed over 18,000 lives. During this pandemic, development of drug resistance further complicated efforts to control and treat the widespread illness. This research utilizes traditional Chinese medicine Database@Taiwan (TCM Database@Taiwan) to screen for compounds that simultaneously target H1 and N1 to overcome current difficulties with virus mutations. The top three candidates were de novo derivatives of xylopine and rosmaricine. Bioactivity of the de novo derivatives against N1 were validated by multiple machine learning prediction models. Ability of the de novo compounds to maintain CoMFA/CoMSIA contour and form key interactions implied bioactivity within H1 as well. Addition of a pyridinium fragment was critical to form stable interactions in H1 and N1 as supported by molecular dynamics (MD) simulation. Results from MD, hydrophobic interactions, and torsion angles are consistent and support the findings of docking. Multiple anchors and lack of binding to residues prone to mutation suggest that the TCM de novo derivatives may be resistant to drug resistance and are advantageous over conventional H1N1 treatments such as oseltamivir. These results suggest that the TCM de novo derivatives may be suitable candidates of dual-targeting drugs for influenza. Citation: Chang S-S, Huang H-J, Chen CY-C (2011) Two Birds with One Stone? Possible Dual-Targeting H1N1 Inhibitors from Traditional Chinese Medicine. PLoS Comput Biol 7(12): e1002315. doi:10.1371/journal.pcbi.1002315 Editor: Kuo-Chen Chou, Gordon Life Science Institute, United States of America Received July 25, 2011; Accepted November 3, 2011; Published December 22, 2011 Copyright: 2011 Chang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The research was supported by grants from the National Science Council of Taiwan (NSC 99-2221-E-039-013-), Committee on Chinese Medicine and Pharmacy (CCMP100-RD-030), China Medical University and Asia University (CMU98-TCM, CMU99-TCM, CMU99-S-02, CMU99-ASIA-25, CMU99-ASIA-26 CMU99ASIA-27 CMU99-ASIA-28). This study is also supported in part by Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH100-TD-B-111004) and Taiwan Department of Health Cancer Research Center of Excellence (DOH100-TD-C-111-005). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: ycc929@MIT.EDU

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