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

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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.

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A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Roujian Lu, Xiang Zhao, Juan Li … (2021)

Summary Background In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. Findings The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. Interpretation 2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.

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Author and article information

Contributors

Burak Berber

Osman Doluca:

ORCID: http://orcid.org/0000-0003-0412-6148

Journal

Journal ID (nlm-ta): Brief Bioinform

Journal ID (iso-abbrev): Brief Bioinform

Journal ID (publisher-id): bib

Title: Briefings in Bioinformatics

Publisher: Oxford University Press

ISSN (Print): 1467-5463

ISSN (Electronic): 1477-4054

Publication date (Electronic): 07 January 2021

Electronic Location Identifier: bbaa379

Affiliations

Eskisehir Technical University, Department of Biology

Massey University , New Zealand

Author notes

Corresponding author: Osman Doluca, Department of Biomedical Engineering, Izmir University of Economics, Izmir 35330, Turkey. E-mail: osman.doluca@ 123456ieu.edu.tr

Author information

Osman Doluca http://orcid.org/0000-0003-0412-6148

Article

Publisher ID: bbaa379

DOI: 10.1093/bib/bbaa379

PMC ID: 7929379

PubMed ID: 33406218

SO-VID: 53b68af9-c866-42ec-bf93-01f900d535a9

License:

This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model ( https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)