Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors

Piermichele Kobauri, Nicole S Galenkamp, Albert M Schulte, Jisk de Vries, Nadja A Simeth, Giovanni Maglia, Sebastian Thallmair, Dušan Kolarski, Wiktor Szymanski*, Ben L Feringa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
10 Downloads (Pure)

Abstract

Photopharmacology uses light to regulate the biological activity of drugs. This precise control is obtained through the incorporation of molecular photoswitches into bioactive molecules. A major challenge for photopharmacology is the rational design of photoswitchable drugs that show light-induced activation. Computer-aided drug design is an attractive approach toward more effective, targeted design. Herein, we critically evaluated different structure-based approaches for photopharmacology with Escherichia coli dihydrofolate reductase (eDHFR) as a case study. Through the iterative examination of our hypotheses, we progressively tuned the design of azobenzene-based, photoswitchable eDHFR inhibitors in five design-make-switch-test-analyze cycles. Targeting a hydrophobic subpocket of the enzyme and a specific salt bridge only with the thermally metastable cis-isomer emerged as the most promising design strategy. We identified three inhibitors that could be activated upon irradiation and reached potencies in the low-nanomolar range. Above all, this systematic study provided valuable insights for future endeavors toward rational photopharmacology.

Original languageEnglish
Article number1c01962
Pages (from-to)4798-4817
Number of pages20
JournalJournal of Medicinal Chemistry
Volume65
Issue number6
Early online date2022
DOIs
Publication statusPublished - 24-Mar-2022

Cite this