Fragment-based drug discovery of photopharmacological agents
File(s)
Author(s)
Tran, Kim Tai
Type
Thesis or dissertation
Abstract
A fundamental challenge for current pharmacotherapy is the lack of drug selectivity that can lead to off-target toxicity and high attrition rates. Photopharmacology is an emerging field that attempts to address this critical issue by employing light-responsive molecules, potentially enabling more precise drug action. However, integrating efficient light-responsiveness with strong target engagement and drug-like features within a single molecule poses a daunting task, and current late-stage approaches that install photoswitchable motifs into established drugs often yield suboptimal outcomes. Here, we show that fragment-based drug discovery can serve as a viable alternative methodology for con-structing photopharmacological agents. In a first study, a large-sized general fragment library was screened against the SARS-CoV-2 methyltransferase NSP16/10, identifying a biarylsulfonamide frag-ment hit B1. Ligand-based fragment optimisation with careful monitoring of target engagement, pho-tochemical properties and lipophilicity ultimately resulted in the photoswitchable lead compound B130, which concurrently displayed a strong single-digit micromolar target affinity, more than an order of magnitude fold change in activity upon photoswitching and an improved lipophilic efficiency. In a second study, the ultra-small and universal fragment probe, 4-bromopyrazole, was employed as a starting point for developing photoswitchable inhibitors against the cancer target, cyclin-dependent kinase 2. Through rational structure-based and computer-aided drug design, the fragment probe was elaborated into a sub-micromolar potent and photoswitchable inhibitor C20 at unprecedented speed. Collectively, these findings suggest that fragments can serve as powerful starting points for achieving multi-parameter optimisation of key photopharmacological properties and arriving at efficient end-points, competitive with those of late-stage approaches. These are the first studies to demonstrate the utility of a fragment-based approach for constructing photoswitchable ligands, and we anticipate that the methodology will aid in addressing the core challenge of reconciling light-responsiveness with drug-like features—ultimately enabling the development of more clinically translatable photopharma-cological agents.
Version
Open Access
Date Issued
2024-05-15
Date Awarded
2024-08-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Fuchter, Matthew
Sponsor
Imperial College London
Commonwealth Scientific and Industrial Research Organization (Australia)
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)