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Methotrexate Inhibits the Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Receptor Binding Domain to the Host-Cell Angiotensin-Converting Enzyme-2 (ACE-2) Receptor.
Kim, Soo-Kyung; Suebka, Sartanee; Gin, Adley; Nguyen, Phuong-Diem; Tang, Yisha; Su, Judith; Goddard, William A.
Afiliación
  • Kim SK; Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, United States.
  • Suebka S; Wyant College of Optical Sciences, The University of Arizona, Tucson, Arizona 85721, United States.
  • Gin A; Wyant College of Optical Sciences, The University of Arizona, Tucson, Arizona 85721, United States.
  • Nguyen PD; Department of Biomedical Engineering, The University of Arizona, Tucson, Arizona 85721, United States.
  • Tang Y; Department of Biomedical Engineering, The University of Arizona, Tucson, Arizona 85721, United States.
  • Su J; Department of Biomedical Engineering, The University of Arizona, Tucson, Arizona 85721, United States.
  • Goddard WA; Wyant College of Optical Sciences, The University of Arizona, Tucson, Arizona 85721, United States.
ACS Pharmacol Transl Sci ; 7(2): 348-362, 2024 Feb 09.
Article en En | MEDLINE | ID: mdl-38357278
ABSTRACT
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus mutates, finding effective drugs becomes more challenging. In this study, we use ultrasensitive frequency locked microtoroid optical resonators in combination with in silico screening to search for COVID-19 drugs that can stop the virus from attaching to the human angiotensin-converting enzyme 2 (hACE2) receptor in the lungs. We found 29 promising candidates that could block the binding site and selected four of them that were likely to bind very strongly. We tested three of these candidates using frequency locked optical whispering evanescent resonator (FLOWER), a label-free sensing method based on microtoroid resonators. FLOWER has previously been used for sensing single macromolecules. Here we show, for the first time, that FLOWER can provide accurate binding affinities and sense the inhibition effect of small molecule drug candidates without labels, which can be prohibitive in drug discovery. One of the candidates, methotrexate, showed binding to the spike protein 1.8 million times greater than that to the receptor binding domain (RBD) binding to hACE2, making it difficult for the virus to enter cells. We tested methotrexate against different variants of the SARS-CoV-2 virus and found that it is effective against all four of the tested variants. People taking methotrexate for other conditions have also shown protection against the original SARS-CoV-2 virus. Normally, it is assumed that methotrexate inhibits the replication and release of the virus. However, our findings suggest that it may also block the virus from entering cells. These studies additionally demonstrate the possibility of extracting candidate ligands from large databases, followed by direct receptor-ligand binding experiments on the best candidates using microtoroid resonators, thus creating a workflow that enables the rapid discovery of new drug candidates for a variety of applications.

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Pharmacol Transl Sci Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Pharmacol Transl Sci Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos