In Silico Evaluation of Sesquiterpenes and Benzoxazinoids Phytotoxins against Mpro, RNA Replicase and Spike Protein of SARS-CoV-2 by Molecular Dynamics. Inspired by Nature

• Published in: Toxins Vol. 14; no. 9; p. 599
• Main Authors: Mejías, Francisco J. R., Durán, Alexandra G., Chinchilla, Nuria, Varela, Rosa M., Álvarez, José A., Molinillo, José M. G., García-Cozar, Francisco, Macías, Francisco A.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 29-08-2022; MDPI
• Subjects: benzoxazinoid; Binding sites; Coronaviruses; COVID-19; Disease transmission; docking; Evaluation; Glycoproteins; Hydrogen bonding; Hydrogen bonds; Ligands; Molecular docking; Molecular dynamics; Natural products; Phytotoxins; Protease; Proteinase; Proteins; Replicase; Respiratory diseases; Ribonucleic acid; RNA; RNA-directed RNA polymerase; SARS-CoV-2; sesquiterpene; Sesquiterpenes; Severe acute respiratory syndrome coronavirus 2; Spike glycoprotein; Spike protein; Stability; Stabilization; Viral infections; Viruses
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins14090599

In the work described here, a number of sesquiterpenes and benzoxazinoids from natural sources, along with their easily accessible derivatives, were evaluated against the main protease, RNA replicase and spike glycoprotein of SARS-CoV-2 by molecular docking. These natural products and their derivatives have previously shown remarkable antiviral activities. The most relevant compounds were the 4-fluoro derivatives of santamarine, reynosin and 2-amino-3H-phenoxazin-3-one in terms of the docking score. Those compounds fulfill the Lipinski’s rule, so they were selected for the analysis by molecular dynamics, and the kinetic stabilities of the complexes were assessed. The addition of the 4-fluorobenzoate fragment to the natural products enhances their potential against all of the proteins tested, and the complex stability after 50 ns validates the inhibition calculated. The derivatives prepared from reynosin and 2-amino-3H-phenoxazin-3-one are able to generate more hydrogen bonds with the Mpro, thus enhancing the stability of the protein–ligand and generating a long-term complex for inhibition. The 4-fluoro derivate of santamarine and reynosin shows to be really active against the spike protein, with the RMSD site fluctuation lower than 1.5 Å. Stabilization is mainly achieved by the hydrogen-bond interactions, and the stabilization is improved by the 4-fluorobenzoate fragment being added. Those compounds tested in silico reach as candidates from natural sources to fight this virus, and the results concluded that the addition of the 4-fluorobenzoate fragment to the natural products enhances their inhibition potential against the main protease, RNA replicase and spike protein of SARS-CoV-2.