Discovery of a Potential Allosteric Site in the SARS-CoV-2 Spike Protein and Targeting Allosteric Inhibitor to Stabilize the RBD Down State using a Computational Approach
- Authors: Li T.1, Yan Z.2, Zhou W.3, Liu Q.3, Liu J.4, Hua H.2
-
Affiliations:
- China Pharmaceutical University,, China Pharmaceutical University
- , The Affiliated Jiangyin Hospital of Nanjing University of Chinese Medicine
- School of Traditional Chinese Pharmacy, China Pharmaceutical University
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University
- Issue: Vol 20, No 6 (2024)
- Pages: 784-797
- Section: Chemistry
- URL: https://rjpbr.com/1573-4099/article/view/644333
- DOI: https://doi.org/10.2174/1573409919666230726142418
- ID: 644333
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Full Text
Abstract
Background:The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide public health crisis. At present, the development of effective drugs and/or related therapeutics is still the most urgent and important task for combating the virus. The viral entry and associated infectivity mainly rely on its envelope spike protein to recognize and bind to the host cell receptor angiotensin-converting enzyme 2 (ACE2) through a conformational switch of the spike receptor binding domain (RBD) from inactive to active state. Thus, it is of great significance to design an allosteric inhibitor targeting spike to lock it in the inactive and ACE2-inaccessible state.
Objective:This study aims to discover the potential broad-spectrum allosteric inhibitors capable of binding and stabilizing the diverse spike variants, including the wild type, Delta, and Omicron, in the inactive RBD down state.
Methods:In this work, we first detected a potential allosteric pocket within the SARS-CoV-2 spike protein. Then, we performed large-scale structure-based virtual screening by targeting the putative allosteric pocket to identify allosteric inhibitors that could stabilize the spike inactive state. Molecular dynamics simulations were further carried out to evaluate the effects of compound binding on the stability of spike RBD.
Result:Finally, we identified three potential allosteric inhibitors, CPD3, CPD5, and CPD6, against diverse SARS-CoV-2 variants, including Wild-type, Delta, and Omicron variants. Our simulation results showed that the three compounds could stably bind the predicted allosteric site and effectively stabilize the spike in the inactive state.
Conclusion:The three compounds provide novel chemical structures for rational drug design targeting spike protein, which is expected to greatly assist in the development of new drugs against SARS-CoV-2.
About the authors
Tong Li
China Pharmaceutical University,, China Pharmaceutical University
Email: info@benthamscience.net
Zheng Yan
, The Affiliated Jiangyin Hospital of Nanjing University of Chinese Medicine
Email: info@benthamscience.net
Wei Zhou
School of Traditional Chinese Pharmacy, China Pharmaceutical University
Email: info@benthamscience.net
Qun Liu
School of Traditional Chinese Pharmacy, China Pharmaceutical University
Author for correspondence.
Email: info@benthamscience.net
Jinfeng Liu
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University
Author for correspondence.
Email: info@benthamscience.net
Haibing Hua
, The Affiliated Jiangyin Hospital of Nanjing University of Chinese Medicine
Author for correspondence.
Email: info@benthamscience.net
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Supplementary files
