Rationalizing Viral Drug Target Identification Using Computational Approaches : The SARS-CoV-2 Spike Glycoprotein S Case Study

COVID-19 emphasized the need for fast reaction tools to fight global biological threats such as viruses. Rapid drug discovery is one of the strategies for efficient social response. The success of a drug discovery campaign critically depends on the selected drug target, and the wrong target nullifies all the efforts to develop a drug. Viral drug target identification is a challenging problem, and computational methods can reduce the number of candidate targets. Here we present a structure-based approach to identify vulnerable regions in viral proteins that comprise drug binding sites. To detect promising binding sites, we take into account protein dynamics, accessibility, and mutability of the binding site, coupled with the putative mechanism of action of a drug. Applying to the SARS-CoV-2 Spike Glycoprotein S, we observed conformation- and oligomer-specific glycan-free binding site that is proximal to the receptor binding domain and comprises topologically important amino acid residues. Molecular dynamics simulations of Spike in complex with drug-like molecules docked into the binding sites revealed shifted equilibrium towards the inactive conformation compared to the ligand-free simulations. Small molecules targeting this binding site could prevent the closed-to-open conformational transition of the Spike protein, thus, allosterically inhibit the interaction with the human angiotensin-converting enzyme 2 receptor.