Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors
Piermichele Kobauri, Nicole Stéphanie Galenkamp, Albert M. Schulte, Jisk de Vries, Nadja A. Simeth, Giovanni Maglia, Sebastian Thallmair, Dušan Kolarski, Wiktor Szymański, Ben L. Feringa
Abstract
High Resolution Image Download MS PowerPoint Slide 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.