Artificial intelligence approach fighting COVID-19 with repurposing drugs

Abstract Background The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19. Material and methods An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in in vitro cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again. Results After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches. Conclusion Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.

[1]  G. Weiss,et al.  Phase I clinical and pharmacokinetic trial of Brequinar sodium (DuP 785; NSC 368390). , 1989, Cancer research.

[2]  S. Paltrinieri Human severe acute respiratory syndrome (SARS) and feline coronaviroses , 2004, Journal of Feline Medicine & Surgery.

[3]  L. Bauer Compounds , 2019, The Oxford Handbook of English Grammar.

[4]  David Rogers,et al.  Extended-Connectivity Fingerprints , 2010, J. Chem. Inf. Model..

[5]  Ying-Ta Wu,et al.  Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors , 2005, Bioorganic & Medicinal Chemistry Letters.

[6]  J. Vederas,et al.  Aryl methylene ketones and fluorinated methylene ketones as reversible inhibitors for severe acute respiratory syndrome (SARS) 3C-like proteinase , 2008, Bioorganic Chemistry.

[7]  Robert P. Sheridan,et al.  Deep Neural Nets as a Method for Quantitative Structure-Activity Relationships , 2015, J. Chem. Inf. Model..

[8]  R. Chang,et al.  Full genome analysis of a novel type II feline coronavirus NTU156 , 2012, Virus Genes.

[9]  S. Deore,et al.  Tissue concentration, systemic distribution and toxicity of clofazimine--an autopsy study. , 2004, Indian journal of pathology & microbiology.

[10]  Herman Tse,et al.  Identification of Novel Small-Molecule Inhibitors of Severe Acute Respiratory Syndrome-Associated Coronavirus by Chemical Genetics , 2004, Chemistry & Biology.

[11]  Xuhui Huang,et al.  Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro , 2020, Antiviral Research.

[12]  L. Reed,et al.  A SIMPLE METHOD OF ESTIMATING FIFTY PER CENT ENDPOINTS , 1938 .

[13]  D. Dexter,et al.  Distribution of the novel anticancer drug candidate brequinar sodium (DuP 785, NSC 368390) into normal and tumor tissues of nude mice bearing human colon carcinoma xenografts , 1988, Cancer Chemotherapy and Pharmacology.

[14]  C. Lindsley,et al.  Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease. , 2013, Journal of medicinal chemistry.

[15]  J. Radhakrishnan,et al.  Capillary leak syndrome: etiologies, pathophysiology, and management. , 2017, Kidney international.

[16]  P. Liang,et al.  Individual and common inhibitors of coronavirus and picornavirus main proteases , 2009, FEBS Letters.

[17]  Wu Zhong,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[18]  S. Barik New treatments for influenza , 2012, BMC Medicine.

[19]  M. Zucchetti,et al.  Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer , 2010, Cancer Chemotherapy and Pharmacology.

[20]  C. Lindsley,et al.  Discovery of N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl)acetamido)phenyl) carboxamides as severe acute respiratory syndrome coronavirus (SARS-CoV) 3CLpro inhibitors: Identification of ML300 and noncovalent nanomolar inhibitors with an induced-fit binding , 2013, Bioorganic & Medicinal Chemistry Letters.

[21]  H. Hsieh,et al.  Pharmacokinetics of Anti-SARS-CoV Agent Niclosamide and Its Analogs in Rats , 2006 .

[22]  E. Freire,et al.  Development of potent dipeptide-type SARS-CoV 3CL protease inhibitors with novel P3 scaffolds: Design, synthesis, biological evaluation, and docking studies , 2013, European Journal of Medicinal Chemistry.

[23]  C. Ling Traditional Chinese medicine is a resource for drug discovery against 2019 novel coronavirus (SARS-CoV-2) , 2020, Journal of Integrative Medicine.

[24]  Thy-Hou Lin,et al.  Discovery of a novel family of SARS-CoV protease inhibitors by virtual screening and 3D-QSAR studies. , 2006, Journal of medicinal chemistry.

[25]  Po-Huang Liang,et al.  Inhibition of SARS-CoV 3C-like Protease Activity by Theaflavin-3,3′-digallate (TF3) , 2005, Evidence-based complementary and alternative medicine : eCAM.

[26]  J. Vederas,et al.  Synthesis and evaluation of keto-glutamine analogues as potent inhibitors of severe acute respiratory syndrome 3CLpro. , 2004, Journal of medicinal chemistry.

[27]  Mitchell A. Avery,et al.  Structure-based virtual screening against SARS-3CLpro to identify novel non-peptidic hits , 2008, Bioorganic & Medicinal Chemistry.

[28]  Min Guan,et al.  Anti-HIV drugs for cancer therapeutics: back to the future? , 2009, The Lancet. Oncology.

[29]  E. Freire,et al.  Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: Structure–activity relationship study , 2013, European Journal of Medicinal Chemistry.

[30]  Xu Shen,et al.  Discovering Severe Acute Respiratory Syndrome Coronavirus 3CL Protease Inhibitors: Virtual Screening, Surface Plasmon Resonance, and Fluorescence Resonance Energy Transfer Assays , 2006, SLAS Discovery.

[31]  N. Stiefl,et al.  A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods. , 2005, Journal of medicinal chemistry.

[32]  N. Pedersen,et al.  Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis , 2019, Journal of feline medicine and surgery.

[33]  Po-Huang Liang,et al.  Structure-based drug design and structural biology study of novel nonpeptide inhibitors of severe acute respiratory syndrome coronavirus main protease. , 2006, Journal of medicinal chemistry.

[34]  Hsuan-Cheng Huang,et al.  Small molecules targeting severe acute respiratory syndrome human coronavirus. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Z. Memish,et al.  The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health — The latest 2019 novel coronavirus outbreak in Wuhan, China , 2020, International Journal of Infectious Diseases.

[36]  Po-Huang Liang,et al.  Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. , 2007, Journal of medicinal chemistry.

[37]  Lisa E. Gralinski,et al.  Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses , 2017, Science Translational Medicine.

[38]  J. Vederas,et al.  Design, synthesis, and evaluation of inhibitors for severe acute respiratory syndrome 3C-like protease based on phthalhydrazide ketones or heteroaromatic esters. , 2007, Journal of medicinal chemistry.

[39]  Shibo Jiang,et al.  Development of Small-Molecule MERS-CoV Inhibitors , 2018, Viruses.

[40]  Xu Shen,et al.  Design and synthesis of cinanserin analogs as severe acute respiratory syndrome coronavirus 3CL protease inhibitors. , 2008, Chemical & pharmaceutical bulletin.

[41]  D. Sykes The emergence of dihydroorotate dehydrogenase (DHODH) as a therapeutic target in acute myeloid leukemia , 2018, Expert opinion on therapeutic targets.

[42]  Sandro G. Viveiros Rosa,et al.  Clinical trials on drug repositioning for COVID-19 treatment , 2020, Revista panamericana de salud publica = Pan American journal of public health.

[43]  N. Pedersen Serologic studies of naturally occurring feline infectious peritonitis. , 1976, American journal of veterinary research.

[44]  Gordon M. Crippen,et al.  Atomic physicochemical parameters for three-dimensional-structure-directed quantitative structure-activity relationships. 2. Modeling dispersive and hydrophobic interactions , 1987, J. Chem. Inf. Comput. Sci..

[45]  Eric D. Brown,et al.  High-Throughput Screening Identifies Inhibitors of the SARS Coronavirus Main Proteinase , 2004, Chemistry & Biology.

[46]  Debbie C. Mulhearn,et al.  Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors , 2008, Bioorganic & Medicinal Chemistry Letters.

[47]  J. Grosset,et al.  Pharmacokinetics and Pharmacodynamics of Clofazimine in a Mouse Model of Tuberculosis , 2015, Antimicrobial Agents and Chemotherapy.

[48]  N. Pedersen,et al.  Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis , 2017, Journal of feline medicine and surgery.

[49]  Arun K. Ghosh,et al.  Structure-based design, synthesis, and biological evaluation of peptidomimetic SARS-CoV 3CLpro inhibitors , 2007, Bioorganic & Medicinal Chemistry Letters.