A comprehensive drug repurposing study for COVID19 treatment: novel putative dihydroorotate dehydrogenase inhibitors show association to serotonin–dopamine receptors

Abstract

Dihydroorotate dehydrogenase (DHODH) is a key enzyme required for de novo pyrimidine synthesis and it is suggested as a target for COVID19 treatment due to high pyrimidine demand by the virus replication in the infected host cells as well as its proven effect of blocking of cytokine release by the immune cells to prevent inflammation leading to acute respiratory distress. There are a number of clinical trials underway for COVID19 treatment using DHODH inhibitors; however, there are only a small number of known DHODH antagonists available for testing. Here, we have applied a methodology to identify DHODH antagonist candidates, and compared them using in silico target prediction tools. A large set of 7900 FDA-approved and clinical stage drugs obtained from DrugBank were docked against 20 different structures DHODH available in PDB. Drugs were eliminated according to their predicted affinities by Autodock Vina. About 28 FDA-approved and 79 clinical trial ongoing drugs remained. The mode of interaction of these molecules was analyzed by repeating docking using Autodock 4 and DS Visualiser. Finally, the target region predictions of 28 FDA-approved drugs were determined through PASS and SwissTargetPrediction tools. Interestingly, the analysis of in silico target predictions revealed that serotonin–dopamine receptor antagonists could also be potential DHODH inhibitors. Our candidates shared a common attribute, a possible interaction with serotonin–dopamine receptors as well as other oxidoreductases, like DHODH. Moreover, the Bruton Tyrosine Kinase-inhibitor acalabrutunib and serotonin–dopamine receptor inhibitor drugs on our list have been found in the literature that have shown to be effective against Sars-CoV-2, while the path of activity is yet to be identified. Identifying an effective drug that can suppress both inflammation and virus proliferation will play a crucial role in the treatment of COVID. Therefore, we suggest experimental investigation of the 28 FDA-approved drugs on DHODH activity and Sars-CoV-2 virus proliferation. Those who are found experimentally effective can play an important role in COVID19 treatment. Moreover, we suggest investigating COVID19 case conditions in patients using schizophrenia and depression drugs.

Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

“…Similar to reports that drug screening is highly dependent on the chosen cell lines and infection conditions (Mirabelli et al, 2021), 17 of the 24 compounds were shown to inhibit SARS-CoV-2 infection in HeLa-ACE2 cells, including reported compounds with broad-spectrum antiviral activity, such as halofuginone, homoharringtonine, salinomycin sodium salt, ouabain, quinacrine 2HCl, and three kinds of dopamine receptor inhibitors (including trifluoperazine 2HCl, pimozide, and prochlorperazine dimaleate salt) (Chen et al, 2021;Ju et al, 2021;Nemerow and Cooper, 1984;Ochiai et al, 1991;Otręba et al, 2020). Dopamine receptor inhibitors have demonstrated broad-spectrum antiviral activity, including against influenza virus, herpes virus, hepatitis C virus, and SARS-CoV-2 (Berber and Doluca, 2021;Nemerow and Cooper, 1984;Ochiai et al, 1991;Otręba et al, 2020). These broad-spectrum antiviral repurposing candidates are of great significance for the treatment of various emerging viral infections.…”

DrugDevCovid19: An Atlas of Anti-COVID-19 Compounds Derived by Computer-Aided Drug Design

“…CADD has seen broad application in drug discovery against COVID-19. In our collected publications, most of them employed docking screen [37][38][39][40][41][42][43], molecular simulation [44], pharmacophore models [45,46], or machine learning-based virtual screens [47] for drug discovery. Docking screen was the most popular one, which took over 96% of the works.…”

A Cartography of Differential Gene Methylation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Different Network Roles in the Protein-Protein Interactions Network Play Different, Biologically Relevant, Roles

“…It is worth noticing that suggestive evidences propose a role for dopamine in Covid-19 pathophysiology (Attademo and Bernardini, 2021b;Berber and Doluca, 2021;Nataf, 2020b). However, dopaminergic antagonists in ME/CFS would may have sedating effect.…”