COVID-19 is caused by the novel enveloped beta-coronavirus with a genomic RNA closely related to severe acute respiratory syndrome-corona virus (SARS-CoV) and is named coronavirus 2 (SARS-CoV-2). The receptor binding domain (RBD) of the S-protein interacts with the human ACE-2 receptor that enables the initiation of viral entry. Hence, blocking the S-protein interactions by means of synthetic compounds mark the pivotal step for targeting SARS-CoV-2. Most of the six compounds were observed to fit nicely with specific noncovalent interactions, including H bonds, electrostatic, Van der Waals and hydrophobic bonds (pi and sigma bonds). Oseltamivir was found to be the most strongly interacting with the RBD, exhibiting high values of full fitness and low free energy of binding. it formed multiple noncovalent bonds in the region of the active site. Hydroxychloroquine also demonstrated high binding affinity in the solvent accessbility state and fit nicely into the active pocket of the S-protein. The results revealed that these compounds could be potent inhibitors of S-protein that could, to some extent, block its interaction with ACE-2. It is obvious from the 3D structure of SARS-CoV-2 spike protein was changed with the interaction of different drugs, which led to the unsuitability to bind ACE2 receptor. Hence, laboratory studies elucidating the action of these compounds on SARS-CoV-2 are warranted for clinical assessments. Chloroquine, hydroxychloroquine and oseltamivir interacted well with the receptor binding domain of S-protein via noncovalent interactions and recommended as excellent candidates for COVID-19.