Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a worldwide pandemic (COVID-19). Drug repurposing studies, including drugs such as dexamethasone (DEX), chloroquine (CQ), and telmisartan (TLS), have been performed in COVID-19 clinical trials. DEX and CQ have been demonstrated in vitro to bind angiotensin-converting enzyme 2 (ACE2), a cellular entry receptor utilized by SARS-CoV-2. However, how DEX/CQ bind to ACE2 and their mechanisms of action are still unknown. We demonstrated that DEX, CQ, and TLS disrupt the interactions between SARS-CoV-2 spike protein and human ACE2 via binding to an allosteric site close to the viral spike protein binding region at the peptidase domain of ACE2, causing a conformational change of the ACE2. We defined four conformational states of ACE2 based on the two helices distances. Our molecular dynamics simulations suggested that binding to the viral spike protein shifted ACE2 conformation populations away from 'Open' conformation. Such conformation population shift is further enhanced by the Delta variant. The binding of the drugs to ACE2 rescues this conformation population shift allosterically to keep ACE2 in 'Open' conformation mostly. Our findings provide a potential insight that modulating the conformation of ACE2 may prevent SARS-CoV-2 invasion due to unfavored poses for spike protein binding.