期刊
VIRUSES-BASEL
卷 12, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/v12050525
关键词
COVID-19; drug repurposing; methylation; methyltransferases; computational screening; molecular docking; molecular dynamics
类别
资金
- Spanish Ministry of Science and Innovation [SAF2016-80639-P]
- Fundacio Oncolliga Girona (Lliga catalana d'ajuda al malalt de cancer, Girona)
- Spanish Ministry of Economy and Competitiveness (MINECO) [RTI2018-096724-B-C21]
- Generalitat Valenciana [PROMETEO/2016/006]
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 respiratory disease pandemic utilizes unique 2 ' -O-methyltransferase (2 ' -O-MTase) capping machinery to camouflage its RNA from innate immune recognition. The nsp16 catalytic subunit of the 2 ' -O-MTase is unusual in its requirement for a stimulatory subunit (nsp10) to catalyze the ribose 2 ' -O-methylation of the viral RNA cap. Here we provide a computational basis for drug repositioning or de novo drug development based on three differential traits of the intermolecular interactions of the SARS-CoV-2-specific nsp16/nsp10 heterodimer, namely: (1) the S-adenosyl-l-methionine-binding pocket of nsp16, (2) the unique activating surface between nsp16 and nsp10, and (3) the RNA-binding groove of nsp16. We employed approximate to 9000 U.S. Food and Drug Administration (FDA)-approved investigational and experimental drugs from the DrugBank repository for docking virtual screening. After molecular dynamics calculations of the stability of the binding modes of high-scoring nsp16/nsp10-drug complexes, we considered their pharmacological overlapping with functional modules of the virus-host interactome that is relevant to the viral lifecycle, and to the clinical features of COVID-19. Some of the predicted drugs (e.g., tegobuvir, sonidegib, siramesine, antrafenine, bemcentinib, itacitinib, or phthalocyanine) might be suitable for repurposing to pharmacologically reactivate innate immune restriction and antagonism of SARS-CoV-2 RNAs lacking 2 ' -O-methylation.
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