Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enter human cells by binding its spike protein receptor-binding domain (S-RBD) with human angiotensin-converting enzyme 2 (hACE2). In the present work, a novel drug-exploring view (food taste: umami) to interfere SARS-CoV-2 S-RBD and one of its variants (Omicron) into human body was explored by an in-silico study. Their interfering interaction and potential mechanism have been illuminated: 1) 34 umami molecules presenting low binding score (< −7 kcal/mol) in molecular docking bonded with active residues of SARS-CoV-2 (Omicron) S-RBD/hACE2 protein by intermolecular interaction (hydrogen bond, hydrophobic interaction and salt bridge, mainly); 2) 4 umami molecules classified in nucleotides and peptides formed relatively stable protein-ligand contacts during molecular dynamic simulation; 3) 3 critical residues (His34, Glu37, and Asp406) remained positive effects in maintaining the ligand-protein structural stability. Taken together, these 4 umami molecules could be supportive as orally bioactive agents for preventing SARS-CoV-2 (Omicron) S-RBD/hACE2 interaction which needs further experimental assays to prove.