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      Two Birds with One Stone? Possible Dual-Targeting H1N1 Inhibitors from Traditional Chinese Medicine

      1 , 2 , 1 , 3 , 4 , 5 , 6 , *

      PLoS Computational Biology

      Public Library of Science

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          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@ 123456Taiwan (TCM Database@ 123456Taiwan ) 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.

          Author Summary

          The influenza A subtype H1N1 (H1N1/09) pandemic raised public concerns due to drug resistance strains. Drug resistance occurs from conformational changes causing the original drug to lose binding ability and exhibit biological effects. The world's largest TCM Database@ 123456Taiwan was employed to screen for potential leads that simultaneously bind to H1 and N1. Three de novo compounds derived from Rosemarinus officinalis and Guatteria amplifolia were identified as having dual binding properties to H1 and N1. Structural analysis indicated that the candidates bind to multiple residues in both H1 and N1. In addition, the de novo derivatives were predicted as bioactive using four different computational models. The compounds are validated as potent dual targeting influenza drug candidates through multiple validations. Key advantages of the candidates include (1) binding to H1 and N1 through multiple amino acids, and (2) not binding to known mutation residues in H1 or N1. Such advantages can reduce drug resistance caused by single point mutations. On a broader context, features important for successful H1N1 drug development are discussed in hopes of providing starting templates for drug development and improvements.

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          Most cited references 124

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          CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983. Copyright 2009 Wiley Periodicals, Inc.
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            Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.
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              Since its identification in April 2009, an A(H1N1) virus containing a unique combination of gene segments from both North American and Eurasian swine lineages has continued to circulate in humans. The lack of similarity between the 2009 A(H1N1) virus and its nearest relatives indicates that its gene segments have been circulating undetected for an extended period. Its low genetic diversity suggests that the introduction into humans was a single event or multiple events of similar viruses. Molecular markers predictive of adaptation to humans are not currently present in 2009 A(H1N1) viruses, suggesting that previously unrecognized molecular determinants could be responsible for the transmission among humans. Antigenically the viruses are homogeneous and similar to North American swine A(H1N1) viruses but distinct from seasonal human A(H1N1).

                Author and article information

                Role: Editor
                PLoS Comput Biol
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                December 2011
                December 2011
                22 December 2011
                : 7
                : 12
                [1 ]Laboratory of Computational and Systems Biology, China Medical University, Taichung, Taiwan
                [2 ]Sciences and Chinese Medicine Resources, China Medical University, Taichung, Taiwan
                [3 ]Department of Bioinformatics, Asia University, Taichung, Taiwan
                [4 ]China Medical University Beigang Hospital, Yunlin, Taiwan
                [5 ]Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America
                [6 ]Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America
                Gordon Life Science Institute, United States of America
                Author notes

                Conceived and designed the experiments: CYCC. Performed the experiments: HJH. Analyzed the data: HJH, SSC. Contributed reagents/materials/analysis tools: CYCC. Wrote the paper: CYCC SSC.

                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.
                Pages: 16
                Research Article
                Computational Biology
                Computer Science
                Computer Modeling
                Drugs and Devices
                Drug Research and Development
                Drug Discovery
                Biophysics Simulations

                Quantitative & Systems biology


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