The utility of sulfonamide group in the design of bifunctional neuraminidase inhibitorsстатьяТезисы
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Дата последнего поиска статьи во внешних источниках: 10 апреля 2019 г.
Аннотация:Neuraminidase (NA) is a membrane protein of influenza virus that plays an essential role in release of progeny virions from host cell surface and constitutes an important target for treatment. Frequent NA mutations confer resistance to its inhibitors (zanamivir, oseltamivir) and make it urgent to develop new medicines. Detection of a so-called 430-cavity nearby the active site of the NA provided an opportunity to develop bifunctional inhibitors which could simultaneously interact with the active site and the above-mentioned cavity. A crucial factor for the inhibitor’s binding in the neuraminidase active site is an interaction with the arginine triad. The required linker of a bifunctional inhibitor should mediate this interaction and provide a stable chemical bond between its fragments. In this work, the utility of a sulfonamide-based linkage and its conformational properties has been studied by computer-aided molecular modeling.
Sulfonamides from ZINC database were used in molecular docking experiments with the Lead Finder software. Next, compounds capable of forming hydrogen bonds between the -SO2-N= functional group and the arginine triad were selected for visual analysis. It was found that the sulfonamide-based linker can interact optimally at the NA boundary between the active site and the 430-cavity, allowing functional fragments of diverse structure to occupy the active site and the 430-cavity. These results demonstrate that proposed linker may be a universal component to construct bifunctional inhibitors out of various structural fragments. To test the hypothesis, several models of zanamivir derivatives containing -SO2-NH-(CH2)n- linker were built, in which zanamivir (first functional fragment) is localized in the NA active site while the second, hydrophobic, fragment is localized in the 430-cavity.
Molecular modeling has shown that sulfonamide linkers may be successfully used for the design of bifunctional NA inhibitors targeted towards both the active site and the 430-cavity.