MD simulation can also be used to calculate the binding free energy of the protein–ligand complex. The binding free energy is the measure of the stability of the system in turns of consistency of nonbonded interactions throughout the simulation. The binding free energy was calculated by using MMPBSA method by taking 2000 snapshots from the trajectory. The computed value of binding free energy for RBD Spro-Piperine is found to be −5.533 ± 0.839 kJ/mol, and for Mpro-Piperine is −37.971 ± 0.271 kJ/mol. It is observed that for both RBD Spro and Mpro, van der Waals energy plays a crucial role in the interaction process. The van der Waals energy, electrostatic energy and non-polar energy are contributed actively to the total interaction energy. In contrast, polar energy has a positive contribution to the whole interaction process. The observed data indicate that the van der Waals, electrostatic and non-polar interactions combinedly contribute to the stability of both the compounds. The contribution from different interactions to the binding free energy for RBD Spro-Piperine and Mpro-Piperine is provided in Supplementary Table S2.