Developing high-affinity drug lead critically depends on the efficient structural optimization of a lead compound. However, the dynamic nature of the process by which drugs bind to target molecules often complicates the rational design of effective substituents, even if their three-dimensional structure is available. Herein, we report a streamlined strategy for the optimization of a galectin-3 binder through the integration of in situ chemistry and native mass spectrometry. This method involves the simultaneous synthesis of multiple analogues in a single reaction vessel, followed by the direct identification of high-affinity derivatives using native mass spectrometry. This approach enables the detection of ligand–protein complexes under native conditions. Through the further structural modification of the identified hit compound, we finally identified high-affinity galectin-3 binders. The results demonstrated that our strategy would reduce the time and effort required for the structural optimization stage of a lead compound.
Hoshi et al. (Thu,) studied this question.