ABSTRACT
Aim: The COVID-19 epidemic, which first emerged in Wuhan in December 2019, rapidly affected the globe in the form of a pandemic, and currently millions of people are classified as active cases in terms of this infection, while tens of thousands of people are in serious or critical conditions. Material and Methods: In this study, 100 lead-like chemical entities were downloaded from the ZINC15 database and subjected to structure-based virtual screening (SBVS) in terms of their potential to be used in combating COVID-19. In our molecular docking study, the Mpro (3CLpro) enzyme encoded by the COVID-19 genome was selected as the receptor molecule that could be targeted in the treatment. Results: A total of 3 small molecules (ZINC000000011271, ZINC000000026220 and ZINC000000006645) were identified as potential inhibitors due to their high binding affinities to this enzyme. Physicochemical profiles of the top-ranked ligands, determined in our study, showed that these compounds were safe and had drug-like features. Furthermore, in molecular dynamics (MD) simulations, the top-ranked compound ZINC000000011271 was found to strongly bound to the Mpro enzyme and preserved its hydrogen bonding stability throughout the whole trajectory. Discussion: In this study, three orphaned drugs (ZINC000000011271, ZINC000000026220 and ZINC000000006646) were found to strongly inhibit Mpro in molecular simulations. These compounds also displayed hit features according to the SwissADME database. Therefore, these hits defined in this study may be used In the development and advanced optimization of potent COVID-19 inhibitors.
ABSTRACT
As of June 2021, the novel coronavirus disease (SARS-CoV-2) resulted in 180 million cases worldwide and resulted in the death of approximately 4 million people. However, an effective pharmaceutical with low side effects that can be used in the treatment of SARS-CoV-2 infection has not been developed yet. The aim of this computational study was to analyze the interactions of twenty-two hydroxycinnamic acid and hydroxybenzoic acid derivatives with the SARS-CoV-2 receptor binding domain (RBD) and host organism's proteases, transmembrane serine protease 2 (TMPRSS2), and cathepsin B and L (CatB/L). According to the RBCI analysis, the ligands with the highest affinity against 4 enzymes in the molecular docking study were determined as 1-caffeoyl-β-D-glucose, rosmarinic acid, 3-p-coumaroylquinic acid and chlorogenic acid. It has also been observed that these compounds interacted more strongly with spike RBD, CatB and CatL enzymes. Although the top-ranked ligand, 1-caffeoyl-β-D-glucose, violated the drug-likeness criteria at 1 point (NH or OH>5) and ADMET in terms of AMES toxicity, the second top-ranked ligand rosmarinic acid neither violated drug-likeness nor exhibited incompatibility in terms of ADMET. In conclusion, with its anti-inflammatory properties, rosmarinic acid can be considered and further investigated as a plant-based pharmaceutical that can offer a treatment option in SARS-CoV-2 infection. However, our findings should be supported by additional in vitro and in vivo studies. © 2008 Universidade Federal do Rio Grande do Sul. All rights reserved.