Computational structure-based drug design: Identifying antivirals from natural products targeting SARS-CoV-2

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which is currently causing an international pandemic belongs to the family of positive-stranded RNA viruses known as Coronaviridae in the order Nidovirales. Coronaviruses, have a long history of causing misery to mankind with their sporadic outbreaks, causing severe human disease and global transmission concerns. The most recent ones include: SARS-CoV (2002); MERS-CoV (2012); and the current SARS-CoV-2 (2019), all of which belong to the genera betacoronavirus. The genome of these viruses is largest among the RNA viruses and is packed inside a helical capsid formed by the nucleocapsid protein (N), which in turn is surrounded by an envelope. The viral envelope protein is further associated with at least three structural proteins: The membrane (M) protein, the envelope (E) protein, and the spike (S) protein. ‘M’ and ‘E’ proteins are mainly involved in virus assembly, whereas the ‘S’ protein mediates virus entry into the host cells. Not surprisingly, the spike protein is the primary focus of the ongoing vaccine efforts as it is involved in binding to the human cell receptors, a critical step in the crosstalk between the virus and host cell. \n Another aspect which is of prime importance but often overlooked is the role of glycans in infection. Enveloped viral pathogens are known to have extensive glycosylation on their capsid and proteins, including the spike protein of coronavirus which has been reported to be highly glycosylated. In fact, recent publications have shown that the spike glycoprotein contains 66 glycosylation sites with 44 of them being included in the model. Previous studies have also indicated site-specific N-linked glycosylation of MERS and SARS S glycoproteins. Moreover, each of these glycosylation sites can be occupied by up to ten different glycans (called glycoforms), greatly extending their epitope diversity.\n In the proposed project we intend to do a detailed mapping of the glycans exhibited by the SARS-CoV-2 and do a comparative analysis to identify conserved glycans among the betacoronavirus genera. The analysis will give us a detailed insight into the variation of the glycans in terms of their structure, density and conservation. In addition, the glycan map will be used to screen the glycan antivirals from the natural source. After successful docking the complex ( SARS-CoV-2-Natural product) will be further subjected to molecular dynamic (MD) simulation studies, to understand the conformational dynamics of the glycan shield of the virus and the bound natural product. The outcome of the project will help us to design cost-effective vaccines. Our study will be a first of its kind which aims at understanding the dynamics of the understudied yet important glycan shield of the coronavirus and help us in identifying and designing a novel cost-effective antiviral compound from the natural source.