key: cord-0884108-e8pn1psp authors: Elzupir, Amin O. title: Inhibition of SARS-CoV-2 main protease 3CL(pro) by means of α-ketoamide and pyridone-containing pharmaceuticals using in silico molecular docking date: 2020-07-10 journal: J Mol Struct DOI: 10.1016/j.molstruc.2020.128878 sha: 53cf929aee2ed601f1541c24cd0d28ad9e503273 doc_id: 884108 cord_uid: e8pn1psp The coronavirus disease infections (COVID-19) caused by a new type of coronavirus (SARS-CoV-2) have been emerging in the entire world. Therefore, it is necessary to find out potential therapeutic pharmaceuticals for this disease. This study investigates the inhibitory effect of the 3-chymotrypsin-like protease of SARS-CoV-2 (3CL(pro)) using pharmaceuticals containing α-ketoamide group and pyridone ring based on molecular docking. Of these, eight pharmaceuticals approved by US-Food and Drug Administration have shown good contact with the catalytic residues of 3CL(pro). They are telaprevir, temsirolimus, pimecrolimus, aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide. Their binding affinity score ranged from -5.6 to -7.4 kcal/mol. Hydrogen bonds were observed and reported. To the knowledge, this study report for the first time a compound that could be binding to ALA(285), the new residue resulting from genetic modification of 3CL(pro) of SARS-CoV-2 that has increased its catalytic activity 3.6-fold compared with its predecessor 3CL(pro) of SARS-CoV. It is recommended that telaprevir, and pyridone-containing pharmaceuticals including aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide be repurposed for COVID-19 treatment after suitable validation and clinical trials. In December 2019, a novel coronavirus named SARS-CoV-2 was reported, after an outbreakpandemic of the pulmonary disease in Wuhan city in China called coronavirus disease-19 . The causes of the first infections were attributed to foods made from bat and batlike animals. Then COVID-19 were melodramatically spread by human-to-human transmission through all the world. As of April 25, 2000 recent studies have shown that the RNA genomes of SARS-CoV-2 are identical to about 82% of that of SARS-CoV [8] [9] [10] [11] . The 229E gene encodes two polyproteins involved in releasing of functional polypeptides, that are essential for viral replication and transcription. The extensive proteolytic processing responsible from the production of the polypeptides is achieved by the 3chymotrypsin-like protease of SARS-CoV-2 (M pro , or 3CL pro ), as it cleaves at least 11 sites on the polyproteins translated from the viral RNA. Thus, drugs that inhibit this enzyme can be an effective therapeutic agent for COVID-19 [12, 13] . Recently several studies have been conducted on some pharmaceuticals, synthetic and natural products to study their ability to inhibit 3CL pro using the molecular docking approach. Of these tested drugs are darunavir, favipiravir isoflavone, myricitrin, chloroquine phosphate, remdesivir, indinavir, valrubicin, lopinavir, carfilzomib, eravacycline, elbasvir, and methyl rosmarinate [14] [15] [16] [17] [18] [19] [20] . Zhang el. have reported α-ketoamide and pyridone containing-synthetic compounds with a good inhibitory effect against 3CL pro [21] . However, more research is still needed in this regard, the aim of this research study was to investigate the inhibitory effect of 3CL pro using approved drugs that contain α-ketoamide group and pyridone ring. The DrugBank database search engine has used to find α-ketoamide and pyridone-containing drugs. Based on these criteria, twelve drugs approved by the U.S. Food and Drug Administration were found. Six of them have α-ketoamide functional group are telaprevir, temsirolimus, pimecrolimus, everolimus, sirolimus, and tacrolimus. While pyridone-containingpharmaceuticals are aminoglutethimide, apixaban, buspirone, lenalidomide, pomalidomide, and ubrogepant. The three-dimensional structures generated and minimized via UCSF Chimera software (v 1.10.2.), using the smile string code offered by the PubChem database. The crystal structure of 3chymotrypsin-like protease (3CL pro ) of SARS-CoV-2 was obtained from the Protein Data Bank database (PDB ID: 6Y2E). sites, and image processing were conducted using UCSF Chimera [22] [23] [24] . The α-ketoamide and pyridone-containing synthetic compound used as a reference in this study docked with 3CL pro containing water residues as a solvent to represents the real environment. It was showed a good inhibitory effect with binding affinity ranged between -5.0 to -6.0 kcal/mole. The chemical structure of the reference compound was monitored in Scheme 1, α-ketoamide functional group and pyridone ring were indicated by blue and red circles, respectively [21] . The search on the DrugBank database revealed that there is no pharmaceutical containing both of the functional groups. Of the α-ketoamide set, everolimus, eirolimus, and tacrolimus have excluded because those drugs were approved as immunosuppressive agents. Whereas, ubrogepant belongs to pyridone containing-drugs was showed no binding affinity to the active residues of CL pro . The binding affinity score of the remaining pharmaceuticals with CL pro were ranged from -5.6 to -7.4 kcal/mol (Tables 1 and 2 ). The inhibitory effect of CL pro was investigated based on hydrogen-bonds and Van der Waals interactions between the selected drugs and the catalytic residues of CL pro (Cys 145 and His 41 ), the important residues for keeping the enzyme on the correct conformation (Ser 1 and Glu 166 ), and the residue resulting from the genetic mutation that led to a 3.6-fold increase in the reproductive effectiveness of the virus (Ala 285 ) [3, 21] . Telaprevir, the anti-hepatitis B virus has the most potent activity among the α-ketoamide-containing drugs. Maybe its activity could be increased by combination use with temsirolimus that used for the treatment of renal cell carcinoma. Figures 1 to 3 show the interactions between these drugs and CL pro , Hydrogen bonds in blue stripes, and Van der Waals yellow stripes. The pyridone-containing pharmaceuticals have shown a tendency to interacts with His 41 and other active residues as shown in Figures 4 to 8 . Of these, aminoglutethimide is used in the treatment of seizures, breast cancer, and prostate cancer [25, 26] . Aminoglutethimide has shown the latest binding affinity, however, is interacts with Cys 145 also and has an ability to make hydrogen bonds with Glu 166 . Buspirone, lenalidomide, and pomalidomide are approved in 1986, 2005, and 2013, respectively. They are used to treat anxiety disorders, multiple myeloma, and anemia [27] [28] [29] . These three medications may be the best inhibitors for CL pro as they have shown a significant tendency to make hydrogen bonds with Cys 145 , however, apixaban may be an exception. Apixaban is approved in 2012 for the prevention and treatment of thromboembolic diseases, its advantage has an ability to bind with the Ala 285 . In this group, the pyridone ring played a key role in inhibiting the CL pro , by making hydrogen bonds with the catalytic residues. The thing that opens the door is wide for many researches into developing new simple inhibitors of this enzyme, as in fact, the pyridone-containing pharmaceuticals are very simple and easy to produce in large commercial quantities commensurate with the spread of this pandemic. To sum, telaprevir, aminoglutethimide, apixaban, buspirone, lenalidomide, and pomalidomide have shown a good binding affinity to the catalytic sites of CL pro . This study suggests the repurposing of these drugs for COVID-19 treatment after a suitable in vitro and in vivo validation as well as clinical trials. To the knowledge, this study report for the first time a 3CL pro inhibitor regarding their contacts with ALA 285 . The author declares that he has no conflict of interest. Amin Osman Elzupir: Idea for work, conceptualization, implementation and paper writing. The data will be available upon request. China Novel Coronavirus Investigating and Research Team. 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