Prophylactic and Therapeutic Potential Zinc Metallodrugs Drug Discovery: Identification of SARS-CoV-2 Replication and Spike/ACE2 Inhibitors.

Abstract

The emergence of severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) variants with novel spike protein mutations has been shown to be influencing the epidemiological and clinical aspects of the COVID-19 pandemic. Due to studies showing various dietary benefits of zinc as a viral replication inhibitor as well as an immunity enhancer, organometallic complexes incorporating zinc ions can be ideal antiviral candidates due to their structural variation and diverse stereochemistry. In silico studies were conducted for the virtual screening of zinc complexes with SARSCoV- 2 and host proteins to explore their effect on viral entry and replication activity. Molegro Virtual Docker along with AutoDock was used for the identification of potential SARS-CoV-2 inhibitor complexes from the Cambridge Structural Database (CSD). Molecular dynamics (MD), density functional theory (DFT), chemical absorption, distribution, metabolism, excretion, and toxicity properties (ADMET) were used to support the findings from virtual screening. In correlation with SARS-CoV-2 RNA-dependent RNA polymerase and spike receptorbinding domain bound with ACE2 docking results, the compound (bis(3,5-dimethyl-1H-pyrazole)- bis(2-furoato)-zinc(ii)) (CSD code ECOZAA) occurs to be a potential metal complex SARS-CoV-2 receptor inhibitor. The compound ECOZAA was observed (in silico binding affinity = - 179.29kcal/mol) to behave better than the clinically approved drug Remdesivir (in silico binding affinity = -62.69kcal/mol) against SARS-CoV-2 RNA-dependent RNA polymerase. The large HOMO- LUMO gap for the ECOZAA compound is an indication of the low chemical reactivity as well as the great kinetic stability of the compound. Thus, this study highlights the potential use of zinc metal complexes as SARS-CoV-2 viral entry and replication inhibitors.