COVID-19,　caused　by　SARS-CoV-2,　is　a　highly　contagious　disease　with　significant　transmissibility　and　pathogenicity.　The　main　protease　of　SARS-CoV-2　(M-pro　or　3CL(pro))　is　crucial　for　viral　replication,　making　it　a　key　therapeutic　target.　Nirmatrelvir,　a　promising　M-pro　inhibitor,　contains　a　trifluoroacetyl　group　in　its　P4　fragment,　which　presents　opportunities　for　further　optimization.　This　study　aims　to　enhance　the　inhibitory　activity　of　nirmatrelvir　through　structural　modification　of　the　P4　fragment.　Using　a　computer-aided　drug　design　(CADD)　approach,　11　novel　compounds　were　identified　based　on　molecular　docking　scores,　binding　free　energy,　predicted　ADMET　properties,　structural　diversity,　synthetic　feasibility,　and　inhibitory　activity.　IC50　measurements　and　molecular　dynamics　(MD)　simulations　demonstrated　significant　inhibitory　potential　for　most　compounds,　with　IC50　values　ranging　from　0.0435-0.9989　mu　M.　Notably,　compounds　2-5a　and　2-5f　exhibited　inhibitory　activity　against　SARS-CoV-2　M-pro　comparable　to　that　of　nirmatrelvir.　These　findings　offer　valuable　insights　for　the　development　of　anti-SARS-CoV-2　therapeutics.