SARS-CoV-2 is the agent responsible for acute respiratory disease COVID-19 and the global pandemic initiated in early 2020. While the record-breaking development of vaccines has assisted the control of COVID-19, there is still a pressing global demand for antiviral drugs to halt the destructive impact of this disease. Repurposing clinically approved drugs provides an opportunity to expediate SARS-CoV-2 treatments into the clinic. In an effort to facilitate drug repurposing, an FDA-approved drug library containing 2400 compounds was screened against the SARS-CoV-2 non-structural protein 7 (nsp7) using a native mass spectrometry-based assay. Nsp7 is one of the components of the SARS-CoV-2 replication/​transcription complex essential for optimal viral replication, perhaps serving to off-load RNA from nsp8. From this library, gallic acid was identified as a compound that bound tightly to nsp7, with an estimated K d of 15 μM. NMR chemical shift perturbation experiments were used to map the ligand-binding surface of gallic acid on nsp7, indicating that the compound bound to a surface pocket centered on one of the protein’s four α-helices (α2). The identification of the gallic acid-binding site on nsp7 may allow development of a SARS-CoV-2 therapeutic via artificial-intelligence-based virtual docking and other strategies.

Understanding molecular level interactions between the metabolome and proteome, two of the most important classes of molecules in biology, will generate deeper insight into the function of metabolites (natural products) which have a central role in interactions with therapeutic targets. Drug discovery in today’s pharmaceutical environment is driven by high-throughput screening of large chemical libraries. It is now 10 years since we published a paper on the development of natural product fraction libraries with control of LogP properties. We have now turned our attention to using pure natural product libraries to address the timeframe issues associated with isolation and characterization of the active constituent(s). Native mass spectrometry can be used as a robust platform for identifying the interactions between natural products and their protein targets. The recent development of Collision-Induced Affinity Selection mass spectrometry, a technique using capture of ligand-protein complexes followed by collision induced dissociation to identify library hits followed by direct ligand-protein confirmation in native mass spectrometry also enables screening of a greater proportion of human proteins. We will review native mass spectrometry-based approaches to use natural product extracts, pre-fractionated natural product libraries and pure natural product libraries for screening against molecular targets. We will also discuss some of the other mass-spectrometry based applications that have been implicated in natural product drug discovery.

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