The protein dynamin, a large GTPase enzyme, has been a central focus of our collaborative research effort for over two decades. In all living cells, dynamin is best known for its essential role in clathrin-mediated endocytosis, where it assembles into collar‑like structures around the necks of budding vesicles following recruitment of the clathrin coat. GTP hydrolysis by dynamin then provides the energy required to release the vesicle from the membrane [1]. Endocytosis is implicated in numerous pathologies including Huntington’s disease, Alzheimer’s disease, stiff‑person syndrome, Lewy body dementia, and epilepsy, and its modulation offers therapeutic potential for neuronal disorders such as chronic pain [2].
Dynamin consists of five functional domains: an N‑terminal GTPase domain, a middle domain, a pleckstrin homology domain, a GTPase effector domain, and a C‑terminal proline‑ and arginine‑rich domain [3]. Chemical biology probes targeting dynamin have provided valuable tools to dissect endocytic pathways [4].
Herein, we report a comprehensive investigation combining synthetic chemistry, molecular modelling, and biological studies to identify distinct small‑molecule interaction regions within dynamin. Our focused chemical libraries include both inhibitors and stimulators derived from diverse scaffolds such as sertralines, arylisoxazoles, and indoles. Structure–activity relationship studies revealed key structural motifs with molecular docking studies suggested potential binding sites. Several structurally diverse analogues exhibited potent activity (IC₅₀ < 10 μM) with some progressed into animal studies, highlighting promising opportunities for future lead development.