Ultra-Large-Scale Screening of Natural Compounds and Free Energy Calculations Revealed Potential Inhibitors for the Receptor-Binding Domain (RBD) of SARS-CoV-2

Abstract

The emergence of immune-evading variants of SARS-CoV-2 further aggravated the ongoing pandemic. Despite the deployments of various vaccines, the acquired mutations are capable of escaping both natural and vaccine-induced immune responses. Therefore, further investigation is needed to design a decisive pharmacological treatment that could efficiently block the entry of this virus into cells. Hence, the current study used structure-based methods to target the RBD of the recombinant variant (Deltacron) of SARS-CoV-2, which was used as a model variant. From the virtual drug screenings of various databases, a total of four hits were identified as potential lead molecules. Key residues were blocked by these molecules with favorable structural dynamic features. The binding free energies further validated the potentials of these molecules. The TBE for MNP was calculated to be −32.86 ± 0.10 kcal/mol, for SANC00222 the TBE was −23.41 ± 0.15 kcal/mol, for Liriodenine the TBE was −34.29 ± 0.07 kcal/mol, while for Carviolin the TBE was calculated to be −27.67 ± 0.12 kcal/mol. Moreover, each complex demonstrated distinct internal motion and a free energy profile, indicating a different strategy for the interaction with and inhibition of the RBD. In conclusion, the current study demands further in vivo and in vitro validation for the possible usage of these compounds as potential drugs against SARS-CoV-2 and its variants.

Discovery of Isojacareubin as a covalent inhibitor of SARS‐CoV‐2 main protease using structural and experimental approaches

“…It is a simulation‐based methodology that has reportedly been shown to be more precise, less expensive, and quicker than traditional approaches just like alchemical method. The method has been previously used for the SARS‐CoV‐2 variants, such as the beta, gamma, delta, and omicron variants, to calculate the BFE 21,45,54,55 . Herein, we calculated the total BFE for each complex and is given in Table 2.…”

“…The method has been previously used for the SARS-CoV-2 variants, such as the beta, gamma, delta, and omicron variants, to calculate the BFE. 21,45,54,55 Herein, we calculated the total BFE for each complex and is given in Table 2. The total BFE for Isojacareubin was calculated to be −64.50 kcal/mol, whereas for…”

Accurate Prediction of Protein-Ligand Interactions by Combining Physical Energy Functions and Graph-Neural Networks

“…The accuracy of these methods varies depending on their computational complexities, with RBFE achieving approximately 1 kcal/mol 6 , while MM-PB/SA typically exhibits an error of a range of 2-3 kcal/mol or even worse 3,7 . Despite their high predictive accuracy, MD-based methods necessitate substantial computational resources and time due to the requirement of generating MD trajectories, which make them unsuitable for ultra-large-scale virtual screening involving more than billions of chemicals 8, 9 .…”