Molecular Docking and Dynamics Simulation Study of Hyrtios erectus Isolated Scalarane Sesterterpenes as Potential SARS-CoV-2 Dual Target Inhibitors

SIMPLE SUMMARY: The ongoing coronavirus disease-2019 (COVID-19) pandemic shows unprecedented challenges for the worldwide healthcare system. Despite the large clinical data concerning several therapeutic interventions and drug repurposing, results are still either preliminary or lacking adequate-clinical efficiency. Herein, different pharmacoinformatics approaches have been adopted such as molecular docking, ADME properties prediction and all-atom MD simulation to investigate several marine-derived scalarane derivatives as lead candidates against two of the major COVID-19 targets; main protease and Nsp15 endoribonuclease. The presented study clearly illustrates the fitness of the proposed scalarane molecules as promising clinical candidates for further development and future in-vitro/in-vivo studies against SARS-CoV-2. ABSTRACT: Presently, the world is under the toll of pandemic coronavirus disease-2019 (COVID-19) outbreak caused by SARS-CoV-2. Lack of effective and safe therapeutics has stressed the scientific community for developing novel therapeutics capable of alleviating and stopping this pandemic. Within the presented study, molecular docking, ADME properties and all-atom molecular dynamic (MD) simulation, along with two standard antiviral agents (lopinavir and benzopurpurin-4B), were applied to investigate 15 scalaranes sesterterpenes natural compounds, purified from the Red Sea marine sponge Hyrtios erectus, as potential COVID-19 dual-target inhibitors. Following multi-step docking within COVID-19 main protease and Nsp15 endoribonuclease cavities, nine promising drug-like compounds exhibited higher docking scores as well as better interactions with the target’s crucial residues than those of reference ligands. Compounds 2, 6, 11, and 15, were predicted to simultaneously subdue the activity of the two COVID-19 targets. Dynamics behavior of the best-docked molecules, compounds 15 and 6, within COVID-19 target pockets showed substantial stability of ligand-protein complexes as presented via several MD simulation parameters. Furthermore, calculated free-binding energies from MD simulation illustrated significant ligand’s binding affinity towards respective target pockets. All provided findings supported the utility of scalarane-based sesterterpenes, particularly compounds 15 and 6, as promising lead candidates guiding the development of effective therapeutics against SARS-CoV-2.