The SARS-CoV-2 virus has caused high-priority health concerns at a global level. Vaccines have stalled the proliferation of viruses to some extent. Yet, the emergence of newer, potentially more infectious, and dangerous mutants such as Delta and Omicron are among the major challenges in finding a more permanent solution for this pandemic. The effectiveness of antivirals Molnupiravir and Paxlovid, authorized for emergency use by the FDA, are yet to be assessed on a larger population. Patients with a high risk of disease progression have received treatment with antibody-cocktail. Most of the mutations leading to the new lineage of SARS-CoV-2 are found in the spike protein of this virus that plays a key role in facilitating host entry. The current study has investigated how to modify a promising peptide-based inhibitor of spike protein, LCB3, against common mutations, N501Y and K417N in the target protein so that it retains its efficacy against the spike protein. LCB3 being a prototype for protein-based inhibitors is an ideal testing system to learn about protein-based inhibitors. This study proposes the substitutions of amino acid residues of LCB3 inhibitor using a structure-based approach that considers free energy decomposition of residues, the distance between atoms, and the interaction among amino acids. The binding free energy calculations suggest a possible improvement in the binding affinity of existing inhibitor LCB3 to the mutant forms of the S-protein using simple substitutions at specific positions of the inhibitor. This approach, being general, can be used in different inhibitors and other mutations and help in fighting against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.