In Silico Discovery of Neutralizing Agents Targeting SARS-CoV-2 Spike Glycoprotein

Author: Scarlet Martinez Cardoze, Onyinyechi Winner Obineche
Mentor: Yoel Rodríguez
Institution: Hostos Community College
Abstract: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first discovered in December 2019 in Wuhan, China, which has caused the pandemic coronavirus disease 2019 (COVID-19) 1,2. The SARS-CoV-2 Spike (S) glycoprotein via its receptor-binding domain (RBD) recognizes the human ACE2 (human Angiotensin-Converting Enzyme 2) receptor facilitating the viral entry into target cells3. There are currently four different variants of SARS-CoV-2 virus worldwide: the D614G variant, the United Kingdom variant (B.1.1.7, N501Y), the Brazil variant (P.1, K417T/E484K/N501Y), and the South Africa variant (B.1.351, K414N/E484K/N501Y). The severity of these variants differs, with the UK variant likely to cause more death due to its higher transmissibility and infectivity1. Despite the available SARC-CoV-2 vaccines, there is still keen need to identify selective antivirals against this virus and the S glycoprotein RBD has been identified as a key target to neutralize the virus. Thus, this research aims to identify small molecules with high-affinity-selectivity for the SARS-CoV-2 S glycoprotein RBD. We hypothesize that these small molecules could disrupt its interaction with hACE2, and therefore affect SARS-CoV-2 replication. To test this hypothesis, we first analyzed the available SARS-CoV-2 S glycoprotein and the hACE2 complex structure (PDB ID 7DF4) and created models for each variant using VMD and MOE programs4. We then started the search of hit compounds by performing structure-based molecular docking virtual screening of a commercially available small molecules database (eMolecules5 ~4.5M compounds) against the four SARS-CoV-2 S glycoprotein RBD models using FRED-4.0.0.0 software. The FRED-4.0.0.0 Chemguass4 scoring function will be used to rank the screened molecules based on their affinities toward SARS-CoV-2 S glycoprotein RBD. The best candidate compounds (~50) will be prioritized to purchase and will be experimentally tested using the SARS-CoV-2 Spike pseudotyped lentivirus assays. These small molecules neutralizing could eventually lead to effective antiviral therapeutic treatment against COVID-19.