Studies on neuraminidase inhibition

• Published in: International journal of quantum chemistry 2018-05, Vol.118 (9), p.n/a
• Main Authors: Paiva, Pedro, Costa, Inês P. D., Ferreira, Cleide E., Ferreira, Pedro, Pereira, Andreia T., Cerqueira, Nuno M. F. S. A., Fernandes, Pedro A., Ramos, Maria J.
• Format: Article
• Language: English
• Subjects: Anchors; AutoDock; Chemistry; Crystal structure; Glutamates; Influenza; Inhibitors; Molecular docking; neuraminidase; Physical chemistry; Quantum physics; Substrates; Viruses
• ISSN: 0020-7608; 1097-461X
• DOI: 10.1002/qua.25592

Neuraminidase (NA) inhibitors are a class of antiviral drugs developed to target the influenza virus— a highly contagious virus that can cause severe respiratory illness and death. Although several NA inhibitors have been developed in the last decade, it is still poorly understood how they interact in the active site of the enzyme and which chemical and structural features potentiate their inhibitory activity. Taking this into account, we analyze in this article the inhibitory activity of 236 known NA inhibitors using molecular docking simulations. The protocol performed in this work, based on AutoDock, demonstrated to be very efficient in differentiating NA inhibitors with ΔGbinding above −11.7 kcal·mol−1. The results have shown that the best inhibitors are those that closely resemble the structure of the natural substrate, but explore additional areas of the active site with which they interact strongly and, therefore, potentiate their inhibitory activity. The best NA inhibitors are characterized by a central saturated six‐member ring filling almost completely the space available in the active site pocket. In addition, they contain both a carboxylate and an acetamide group, bound to the central ring structure, which allow them to interact with five arginines, organized in a triad (Arg371, Arg118, Arg292) and a pair (Arg151, Arg152). These interactions are very strong and act as two anchors that fix the compounds in the active site. The inhibitory activity of the compounds is improved if they have hydrophobic groups pointing toward a hydrophobic region of the active site, where Ile222 is located, and when they have amine or guanidine groups pointing toward three glutamates (Glu277, Glu276, Glu227). The studies performed here lay the foundations for the rational design of new and more efficient drugs to fight the influenza virus. Influenza virus infections account for significant morbidity and healthcare expenditures worldwide. Several influenza virus inhibitors are known to act through the inhibition of neuraminidase, a glycoprotein crucial for the infection of new host cells. Using molecular docking simulations, this work analyzes the chemical and structural features of 236 known neuraminidase inhibitors. The conclusion gathered in this study incites future rational design campaigns of new and more efficient drugs to fight the influenza virus.