The CORDITE database contains aggregated information from published and preprint articles about potential drugs, their targets and their interactions (Martin et al. 2020). Different computational approaches reveal drug candidates that may be repurposed for the Covid-19 pandemic. The data provide by this database should be treated as interesting starting points for approved drug candidates that would require clinical testing to determine their efficacy specifically in Covid-19 patients. Here, potential drug candidates for the human ACE2 receptor are described.
Fan et al. constructed a pangolin coronavirus model to screen 2406 approved drugs for their ability to inhibit cytopathic effects and thereby identify candidates for treating Covid-19 infection (Fan et al. 2020). Three drugs, cepharanthine, selamectin and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture. Selamectin is excluded from inclusion here as it is a vetinary drug not approved for human use.
Using Human Pluripotent Stem Cell-derived Colonic Organoids (hPSC-COs) and humanized mouse models, Duan et al. 2020 screened 1280 FDA-approved drugs, which uncovered mycophenolic acid and quinacrine dihydrochloride as promising candidates for SARS-CoV-2 entry inhibition, with greater efficacy than drugs currently being investigated for therapeutic use in COVID-19 (preprint https://www.biorxiv.org/content/10.1101/2020.05.02.073320v1.full).
Molecular dynamic simulations of SARS-CoV-2 spike protein and human ACE2 receptor complexes with stilbenoid analogues potentially having activities against these targets revealed resveratrol to have good affinity for the spike:ACE2 complex. Resveratrol could be a promising anti-COVID-19 drug candidate acting through disruption of the spike protein (Wahedi et al. 2020).
Using a virtual screen of the main targets involved in Covid-19 infection with 7922 FDA-approved drugs, Durdagi et al. 2020 ranked compounds based on their docking scores. Promising ACE2 receptor-binding domain inhibitors included denopamine and rotigaptide amongst the top 5 hits. These compounds could be clinically tested to check whether they may be considered to be use for the treatment of COVID-19 patients (preprint https://chemrxiv.org/articles/preprint/Screening_of_Clinically_Approved_and_Investigation_Drugs_as_Potential_Inhibitors_of_COVID-19_Main_Protease_A_Virtual_Drug_Repurposing_Study/12032712).
Using an in-silico structure-based virtual screening approach, Choudhary et al. 2020 found the FDA-approved drug eptifibatide acetate bound to the virus binding motifs of the ACE2 receptor (preprint https://chemrxiv.org/articles/preprint/Identification_of_SARS-CoV-2_Cell_Entry_Inhibitors_by_Drug_Repurposing_Using_in_Silico_Structure-Based_Virtual_Screening_Approach/12005988).
Redka et al. 2020 utilised a deep learning drug design platform to interrogate the polypharmacological profiles of FDA-approved small molecule drugs or going through clinical trials, with the goal of identifying molecules predicted to modulate targets relevant for COVID-19 treatment. Top drug hits predicted to bind to the ACE2 receptor included a number of broad-spectrum antibiotics such as latamoxef, cefazolin, cefoxitin, enoxacin and pheneticillin, amongst others. This study may identify and prioritise candidates for testing in Covid-19 patients (preprint https://chemrxiv.org/articles/preprint/PolypharmDB_a_Deep_Learning-Based_Resource_Quickly_Identifies_Repurposed_Drug_Candidates_for_COVID-19/12071271)
In a study mining electronic health records, usage of diphenhydramine, hydroxyzine and azelastine was associated with reduced incidence of SARS-CoV-2 positivity in subjects greater than age 61 (Reznikov et al, 2020). Generally lower COVID19 incidence in people taking antihistamines was seen in a large observational study (Vila-Córcoles et al, 2020). Subsequently it was found that several H1 receptor antagonists are potent ACE2 inhibitors and potential COVID19 therapeutics: hydroxyzine (Reznikov et al, 2020) azelastine (Reznikov et al, 2020; Ge et al, 2021a), doxepin (Ge et al, 2021b), loratadine and desloratadine (Hou et al, 2021).