Mechanistic Insights of Polyphenolic Compounds from Rosemary Bound to Their Protein Targets Obtained by Molecular Dynamics Simulations and Free-Energy Calculations

Rosemary represents an important medicinal plant that has been attributed with various health-promoting properties, especially antioxidative, anti-inflammatory, and anticarcinogenic activities. Carnosic acid, carnosol, and rosmanol, as well as the phenolic acid ester rosmarinic acid, are the main compounds responsible for these actions. In our earlier research, we carried out an inverse molecular docking at the proteome scale to determine possible protein targets of the mentioned compounds. Here, we subjected the previously identified ligand–protein complexes with HIV-1 protease, K-RAS, and factor X to molecular dynamics simulations coupled with free-energy calculations. We observed that carnosic acid and rosmanol act as viable binders of the HIV-1 protease. In addition, carnosol represents a potential binder of the oncogene protein K-RAS. On the other hand, rosmarinic acid was characterized as a weak binder of factor X. We also emphasized the importance of water-mediated hydrogen-bond networks in stabilizing the binding conformation of the studied polyphenols, as well as in mechanistically explaining their promiscuous nature.