Phthalocyanine and hypericin have been previously identified as possible SARS-CoV-2 Spike glycoprotein fusion inhibitors through a virtual screening procedure. In this paper, atomistic simulations of metal-free phthalocyanines and atomistic and coarse-grained simulations of hypericins, placed around a complete model of the Spike embedded in a viral membrane, allowed to further explore their multi-target inhibitory potential, uncovering their binding to key protein functional regions and their propensity to insert in the membrane. Following computational results, pre-treatment of a pseudovirus expressing the SARS-CoV-2 Spike protein with low compounds concentrations resulted in a strong inhibition of its entry into cells, suggesting the activity of these molecules should involve the direct targeting of the viral envelope surface. The combination of computational and in vitro results hence supports the role of hypericin and phthalocyanine as promising SARS-CoV-2 entry inhibitors, further endorsed by literature reporting the efficacy of these compounds in inhibiting SARS-CoV-2 activity and in treating hospitalized COVID-19 patients.Communicated by Ramaswamy H. Sarma.
Keywords: SARS-CoV-2; fusion inhibitors; hypericin; molecular simulations; phthalocyanine; pseudovirus antiviral assay.