Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a coronavirus that has caused a pandemic designated Coronavirus Disease 2019 (COVID-19) [1
]. This virus is transmitted byrespiratory secretions between humans by direct contact or respiratory droplets. Most infected individuals suffer a mild disease or are asymptomatic. However, elderly people with comorbidities, such as diabetes, hypertension, and obesity, are prone to severe pulmonary disease that can cause death. The numbers of cases with severe disease complications are surpassing the capacity of health services around the world. This makes the disease a worrisome threat for public health services worldwide. Due to its recent origin related to bats [2
], there is no specific treatment to combat the SARS-CoV-2 virus.
The SARS-CoV-2 genome produces 16 non-structural proteins and four structural proteins: spike (S), nucleocapsid (N), membrane (M) and envelope (E). These structural proteins are involved in virus survival within host cells [3
]. Due to their evident importance, these proteins are suitable targets to develop new drugs for a pharmacological treatment. Several studies have used drug repurposing strategies that focus on the mechanism of entry, replication, and other viral targets to rapidly identify potential therapeutics [4
]. The study by Kumar and Singh, using a small subset of 75 FDA antiviral drugs, found that the antivirals, lopinavir-ritonavir, tipranavir and raltegravir, could bind to SARS-Cov-2 Mpro with similar binding affinity to the inhibitor N3 [5
]. Attempts to identify potential scaffolds were made with a pharmacophore model and Activity Cliff Analysis [6
]. Thirty-eight structurally diverse compounds were analyzed using a nuclear magnetic resonance (NMR) fragment-based approach, which identified triclabendazole, emedastine and omeprazole as potential Mpro inhibitors. Oxytetracycline and other twelve structurally potential inhibitors were also identified with a virtual screening approach using 7 million drug-like compounds from the ZINC15 database [7
]. Additionally, 23 drugs from 12 different groups were evaluated using an infected cell-based assay, where hydroxychloroquine and azithromycin were the most promising compounds [8
]. Another study found withaferin A and artesunate as promising SARS-CoV-2 Mpro inhibitors [9
]. Moreover, other compounds have been tested for inhibition using computational models. For example, the interface of S protein in its human receptor ACE2 was used as a target to repurpose 47 compounds, applying an in silico docking protocol [10
]. The same approach was applied to the prediction of SARS-CoV-2 main protease (Mpro) inhibitors that are also involved in the replication and transcription of the virus [11
]. Some methodologies are based on a consensus score strategy using two different docking tools [13
] or molecular dynamics (MD) simulation [15
]. The use of molecular dynamics is useful for binding the free energy calculations and have been used to identify key interacting residues of Mpro in protein-ligand complex analysis [15
Although SARS-CoV-2 Mpro has been previously analyzed in silico, pre-print studies already mentioned did not explore the wide chemical space available for testing repurposing computational protocols. Hence, in this study, we expand the drug predictions to inhibit SARS-CoV-2 Mpro by mining the PDB, ChEMBL, BindingDB and DrugBank databases through a virtual screening protocol with a combination of ligand-based and structure-based approaches. To this end, different cheminformatics and molecular modeling techniques were applied according to the information retrieved from each database. As a result, we obtained potential drug candidates different from previous reports that could inhibit the SARS-CoV-2 Mpro protein.