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

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.

Design and various in silico studies of the novel curcumin derivatives as potential candidates against COVID-19 -associated main enzymes

“…This method is one of the most commonly used methods to determine the accuracy of a docking protocol. In this context, a docking method can be considered valid if the RMSD value between superimposed configurations of ligands is ≤ 2.0 Å ( Abdusalam and Murugaiyah, 2020 , Azam, 2021 , C et al, 2022 , Elhady et al, 2021 ). Accordingly, our results show that all reference inhibitors overlap almost perfectly with RMSD values obtained within these limits, therefore it can be said that our docking protocol is valid.…”

β-Blockers bearing hydroxyethylamine and hydroxyethylene as potential SARS-CoV-2 Mpro inhibitors: rational based design,in silico,in vitro, and SAR studies for lead optimization

“…This was in great concordance with our previous study investigating promising natural scalaranes sesterterpenes isolated from the Red Sea marine sponge Hyrtios erectus as promising inhibitors of SARS-CoV-2 Mpro target. 46 Moving towards the S1 subsite, significant high ΔRMSF values were depicted across the four ligand–bound proteins regarding a couple of pocket lining residues, His-163 and Glu-166. Significant immobility for the Glu-166 ensures the reported data in current literature suggesting the crucial role of S1 subsite Glu-166 residues for stabilizing several drug-like and peptidomimetic ligands at the Mpro active site.…”

Investigating the structure–activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors

“…This was in great concordance with our previous study investigating promising natural scalaranes sesterterpenes isolated from the Red Sea marine sponge Hyrtios erectus as promising inhibitors of SARS-CoV-2 Mpro target. 77 …”

“…Models showing the best docking scores of the most promising leads, as well as reference ligands (O6K and N3) in complex with SARS-CoV-2 Mpro, were chosen as starting coordinates for 200 ns all-atom molecular dynamics simulation using the GROMACS-2019 software package. 77,78 The symmetry operations (rotations and translations) by the VMD software were applied using the transformation matrices within the PDB crystalline files to obtain the ligand–Mpro dimers. Parameterization of all investigated ligands and generation of their respective topology files were automatically generated using the CHARMM-General Force Field program (Param-Chem project; ).…”