TY - GEN
T1 - Allosteric Modulation of Small Molecule Drugs on ACE2 Conformational Change upon Binding to SARS-CoV-2 Spike Protein
AU - Wang, Duen Shian
AU - Hayatshahi, Hamed S.
AU - Jayasinghe-Arachchige, Vindi M.
AU - Liu, Jin
N1 - Publisher Copyright:
© 2021 IEEE.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - ACE2 conformational change
KW - Delta variant
KW - SARS-CoV-2
KW - allosteric
KW - chloroquine
KW - dexamethasone
KW - telmisartan
UR - http://www.scopus.com/inward/record.url?scp=85125119671&partnerID=8YFLogxK
U2 - 10.1109/BIBM52615.2021.9669438
DO - 10.1109/BIBM52615.2021.9669438
M3 - Conference contribution
AN - SCOPUS:85125119671
T3 - Proceedings - 2021 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2021
SP - 2587
EP - 2594
BT - Proceedings - 2021 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2021
A2 - Huang, Yufei
A2 - Kurgan, Lukasz
A2 - Luo, Feng
A2 - Hu, Xiaohua Tony
A2 - Chen, Yidong
A2 - Dougherty, Edward
A2 - Kloczkowski, Andrzej
A2 - Li, Yaohang
PB - Institute of Electrical and Electronics Engineers Inc.
Y2 - 9 December 2021 through 12 December 2021
ER -