Resources and computational strategies to advance small molecule SARS-CoV-2 discovery: Lessons from the pandemic and preparing for future health crises

Abstract

There is an urgent need to identify new therapies that prevent SARS-CoV-2 infection and improve the outcome of COVID-19 patients. This pandemic has thus spurred intensive research in most scientific areas and in a short period of time, several vaccines have been developed. But, while the race to find vaccines for COVID-19 has dominated the headlines, other types of therapeutic agents are being developed. In this mini-review, we report several databases and online tools that could assist the discovery of anti-SARS-CoV-2 small chemical compounds and peptides. We then give examples of studies that combined in silico and in vitro screening, either for drug repositioning purposes or to search for novel bioactive compounds. Finally, we question the overall lack of discussion and plan observed in academic research in many countries during this crisis and suggest that there is room for improvement.

Fig. 1

The virtual screening workflow for the identification and development of COVID-19 treatments using different drug discovery tools. This figure was inspired by the study reported here .

Fig. 2

Chemical structures of small molecule inhibitors and peptides that are active against the SARS-CoV-2 virus. 1, N3, 2, Ebselen 3, Disulfiram 4, Tideglusib 5, Carmofur 6, Shikonin 7, PX-12 8, TDZD-8 9, Cinanserin 10, N-((S)-3-cyclohexyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)-1H-indole-2-carboxamide 11, N-((S)-3-(3-fluorophenyl)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)-1H-indole-2-carboxamide 12, Manidipine 13, Boceprevir 14, Lercanidipine 15, Efonidipine 16, Bedaquiline 17, Carprofen 18, Celecoxib 19, Lumacaftor 20, Cepharanthine 21, Baricitinib 22, Diminazene 23, 4,4′-((Z)-6-(((E)-3-methylbenzylidene)hydrazono)-3,6-dihydropyrimidine-2,4-diyl)dimorpholine 24, Hypericin 25, Cyanidin-3-O-glucoside 26, SRT2104 27, Amiodarone 28, Bosutinib 29, Clofazimine 30, Entecavir 31, Fedratinib 32, Gilteritinib 33, Lactoferrin (the peptide segment expected to be important) 34, Lomitapide 35, Metoclopramide 36, Niclosamide 37, Remdesivir 38, S1RA 39, Thioguanine 40, Verapamil 41, Z-FA-FMK, 42, GC376 43, Quercetin. It is important to note that some of these molecules (e.g., Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin) could be nonspecific promiscuous compounds (see [229]).