The curcumin derivative with the best binding affinity was Bis-demethoxycurcumin for both 6CRV (ΔG = −10.98 kcal/mol) and 6M0J (ΔG = −10.01 kcal/mol). The native compound, curcumin, demonstrated a binding energy of −9.81 kcal/mol for 6M0J and −10.1 kcal/mol for 6CRV. Binding mode of Bis-demethoxycurcumin with SARS-CoV Spike protein and SARS-CoV-2 Spike protein RBD is shown in Figure 2 and 3, respectively.