Identification of potential hits against novel coronavirus-targeting glycoprotein for multi-target approach

ABSTRACT

Coronavirus disease (COVID-19) is an infectious disease caused by a novel coronavirus impacting more than 75 million people across 220 countries. The pharma and biotech industries, along with research institutes, strive to develop an effective vaccine against the novel coronavirus. Efforts are also underway for finding drugs through drug repurposing and novel drug discovery methods. In this study, we have used a multi-target drug approach. The objective is to identify phytochemicals from plant sources effective against novel coronavirus. Natural products having good medicinal properties are known to have minimal side effects compared to synthetic drugs. Therefore, the medicinal products from natural sources are of significance in drug discovery research. In this study, compounds from three common plants were selected for analysis, namely, Tinospora cordifolia, Withania somnifera, and Punica granatum. The primary target selected for this study was glycoprotein. Glycoproteins are known to play a key role in the regulation of cell proliferation, growth, and signaling pathways. We also investigated the effect of screened compounds on other targets in order to have a multi-target therapy. The target proteins chosen for drug design are Spike glycoprotein, Main Protease, and uridylate-specific Endoribonuclease (EndoU). The spike glycoprotein (S) of coronavirus, is a trimeric transmembrane protein, which facilitates entry into cells and is the main target of antibodies. The spike glycoprotein is highly sensitive to mutation. The main protease (MPro) of SRAS-CoV-2 plays an essential role in disease propagation by processing the polyproteins necessary for its replication. Inhibiting the main protease by designing agonists/antagonists can serve in the repair mechanism-the uridylate-specific Endoribonuclease (EndoU) of SRAS-CoV-2 causes a delay in the host sensor system. The objective of this study was to identify potential natural hit compounds which could target multiple proteins of coronavirus. Compounds that can target all the three, namely, Spike glycoprotein, EndoU, and MPro will have better therapeutic index and efficacy than a single target approach. Therefore, the compounds were screened against all these three structural targets. The compounds targeting only one of the proteins were filtered and only those compounds showing activity against all the three structural proteins were retained for further analysis. Drug design methods, including Absorption, Distribution, Metabolism and Elimination (ADME) profiling and molecular docking studies, have been used in the study to identify potential hit molecules. The twenty four hits obtained targeted all the three selected proteins. This will pave the way for developing lead molecules from the screened compounds effective against all three proteins of novel coronavirus Main protease, Spike glycoprotein, and Endoribonuclease.