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The emergence of pandemic situations originated from SARS-CoV-2 and its new variants created worldwide medical emergencies. Due to the non-availability of efficient drugs and vaccines, hundreds of thousands of people succumbed to death intoxicated by this virus. At these emergency hours, repurposing existing drugs can effectively treat patients critically infected by SARS-CoV-2. Using a high-throughput screening approach, we validated a list of potential repurposed drugs, like Nafamostat, Camostat, Silmitasertib, Valproic acid, Zotatifin, and essential host target proteins HDAC2, eIF4E2, CSK22, that are essential for viral mechanism. We determined multiple dissociation pathways of repurposed drugs, suggesting the availability of sub pockets within the host target proteins. We showed the preferential residues involved in the (un)binding kinetics of the ligands correlated to the underlying mechanism of the host protein activity. Interestingly, the residues we obtained for HDAC2 and CSK22 target proteins, which we highlighted, are also involved in the catalytic activity. The mechanistic insight presented in this work is envisaged to help use these key host proteins and potential repurposed drugs as a treatment for the SARS-CoV-2 virus.