Repurposing of FDA-Approved Toremifene to Treat COVID-19 by Blocking the Spike Glycoprotein and NSP14 of SARS-CoV-2

Abstract

The global pandemic of Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to the death of more than 675,000 worldwide and over 150,000 in the United States alone. However, there are currently no approved effective pharmacotherapies for COVID-19. Here, we combine homology modeling, molecular docking, molecular dynamics simulation, and binding affinity calculations to determine potential targets for toremifene, a selective estrogen receptor modulator which we have previously identified as a SARS-CoV-2 inhibitor. Our results indicate the possibility of inhibition of the spike glycoprotein by toremifene, responsible for aiding in fusion of the viral membrane with the cell membrane, via a perturbation to the fusion core. An interaction between the dimethylamine end of toremifene and residues Q954 and N955 in heptad repeat 1 (HR1) perturbs the structure, causing a shift from what is normally a long, helical region to short helices connected by unstructured regions. Additionally, we found a strong interaction between toremifene and the methyltransferase nonstructural protein (NSP) 14, which could be inhibitory to viral replication via its active site. These results suggest potential structural mechanisms for toremifene by blocking the spike protein and NSP14 of SARS-CoV-2, offering a drug candidate for COVID-19.

Keywords: COVID-19; SARS-CoV-2; drug repurposing; methyltransferase nonstructural protein 14 (NSP14); molecular docking; spike glycoprotein; toremifene.

Figure 1:. A diagram illustrating the workflow of computational identification of viral targets of toremifene across the SARS-CoV-2 proteome.

Toremifene (center) with potential targets for molecular docking. From top right: PL-PRO, papain-like protease; NSP4, non-structural protein 4; NSP9, non-structural protein 9; RNA-P, RNA-directed RNA polymerase; NSP15, non-structural protein 15; NSP16, non-structural protein 16; NSP14, non-structural protein 14; Spike, spike glycoprotein.

Figure 2:. Toremifene likely interacts with the spike glycoprotein of SARS-CoV-2.

(a) The full-length crystal structure (PDB ID: 6VSB) of the homotrimeric spike glycoprotein with toremifene. (b) The final conformation of toremifene (blue, ball and stick) with the spike glycoprotein at 500 nanoseconds of simulation. (c) Key interacting residues with toremifene. Edges are labeled with MM/PBSA interaction energies.

Figure 3:. Toremifene likely displaces functional ligands in NSP14 in SARS-CoV-2.

(a) The homology model of NSP14 with toremifene. (b) Key interacting residues with toremifene, with edges labeled with MM/PBSA interaction energy. (c) Final pose of toremifene (blue, ball and stick) with NSP14 at 500 nanoseconds of simulation. The RMSD for all simulations can be found in Supplementary Figure 7.

Figure 4:. Toremifene interacts with the spike glycoprotein and NSP14.

Stick representations of the final pose at 500 nanoseconds for toremifene with (a) the spike glycoprotein and (b) NSP14. Wireframe residues represented in each image are within 3.0 angstroms of toremifene in the final frame of the 500 nanosecond (ns) simulation.