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

Soo Kyung Kim, Sartanee Suebka, Adley Gin, Phuong Diem Nguyen, Yisha Tang, Judith Su, William A. Goddard

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)348-362
Number of pages15
JournalACS Pharmacology and Translational Science
Volume7
Issue number2
DOIs
StatePublished - Feb 9 2024

Keywords

  • COVID-19
  • DarwinDock
  • FLOWER
  • SARS-CoV-2
  • hACE2
  • in silico drug design
  • methotrexate
  • microtoroid
  • virtual screening
  • whispering gallery mode

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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