Exploring the chemical space of influenza neuraminidase inhibitors
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Abstract
The fight against the emergence of mutant influenza strains has led to the screening of an increasing number of compounds for inhibitory activity against influenza neuraminidase. This study explores the chemical space of neuraminidase inhibitors (NAIs), which provides an opportunity to obtain further molecular insights regarding the underlying basis of their bioactivity. In particular, a large set of 347 and 175 NAIs against influenza A and B, respectively, was compiled from the literature. Molecular and quantum chemical descriptors were obtained from low-energy conformational structures geometrically optimized at the B3LYP/6-31G(d) level. The bioactivities of NAIs were classified as active or inactive according to their half maximum inhibitory concentration (IC50) value in which IC50 < 1 μM and > 10 μM were defined as active and inactive compounds, respectively. Interpretable decision rules were derived from a quantitative structure-activity relationship (QSAR) model established using a set of 13 descriptors via decision tree analysis. Good predictive performance was achieved as deduced from 10-fold cross-validation, in which an accuracy and MCC of 82.46% and 0.649, respectively, were obtained for influenza A NAIs while values of 80.00% and 0.553 were obtained for influenza B NAIs. Both univariate and multivariate analyses revealed the importance of the lowest unoccupied molecular orbital, number of hydrogen bond donors and number of hydrogen bond acceptors in the predictive model of NAIs against influenza A while the number of hydrogen bond acceptors, molecular energy and the energy gap between the highest occupied and lowest unoccupied molecular orbitals were important in the predictive model for influenza B NAIs. Molecular scaffold analysis was performed on both data sets for discriminating important structural features among active and inactive NAIs. Furthermore, molecular docking was employed to investigate the binding modes and their moiety preferences of active NAIs against both influenza A and B neuraminidase. Moreover, novel NAIs with robust binding fitness towards influenza A and B neuraminidase were generated via combinatorial library enumeration and their binding fitness was on par or better than FDA-approved drugs. The results from this study are anticipated to be beneficial for guiding the rational drug design of novel NAIs for treating influenza infections.
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2016. Exploring the chemical space of influenza neuraminidase inhibitors. PeerJ PrePrints 4:e1554v2 https://doi.org/10.7287/peerj.preprints.1554v2note This preprint is not peer-reviewed. You may wish to reference the subsequent peer-reviewed version of this article.
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This is a revision made according to comments from the peer-reviewers.
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Competing Interests
The authors declare that they have no competing interests.
Author Contributions
Nuttapat Anuwongcharoen performed the experiments, analyzed the data, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Watshara Shoombuatong performed the experiments, analyzed the data, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Tanawut Tantimongcolwat analyzed the data, wrote the paper, reviewed drafts of the paper.
Virapong Prachayasittikul analyzed the data, contributed reagents/materials/analysis tools, wrote the paper, reviewed drafts of the paper.
Chanin Nantasenamat conceived and designed the experiments, analyzed the data, contributed reagents/materials/analysis tools, wrote the paper, prepared figures and/or tables, reviewed drafts of the paper.
Data Deposition
The following information was supplied regarding data availability:
Data sets (CSV file format) and molecular structures (SDF file format) of enumerated ligands are available as a supplementary data on figshare at http://dx.doi.org/10.6084/m9.figshare.1612484
Funding
This research project is supported by the Office of Higher Education Commission and Mahidol University under the National Research Universities Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
