Multiscale modelling and structure-guided development of small molecules tackling neuroinflammation and inflammageing

Abstract

Early diagnosis and treatment of neurodegenerative diseases has gained attention, given their increasing prevalence. Multiple proteins are currently being investigated as novel targets for drug development, including α7 nicotinic receptors and mitochondrial translocator protein TSPO. These proteins play an important role in neuroinflammation, which makes them attractive for development of drugs and diagnostics. However, small molecule development has been hampered by existence of a human-specific dupa7 isoform, and an A147T-TSPO polymorph, which present a challenge for development of potent and selective ligands. In this work, I characterised the structure and dynamics of the most plausible functional a7 pentamers bearing dupα7 subunits. The receptors have been modelled and assessed using multiscale molecular dynamics (MD) simulations and enhanced sampling techniques. The energy landscapes of the pentamers with different stoichiometries showed that receptors with a low ratio of dupα7/α7 remained functional. Sensitivity of dupa7 receptors to an antagonist (α- BTX) and amyloid Aβ42 has also been assessed. Further, putative “druggable” binding sites at dupα7 receptors were mapped, and interactions between dupα7 and small molecules were explored using a combination of solvent mapping, MD simulations, and molecular docking. Results indicated that neither established orthosteric agonist nor allosteric ligands can bind to dupα7/dupα7 interfaces, however, α7/dupα7 interfaces remain “druggable”. In addition, several novel allosteric sites were detected on α7/dupα7 receptors. The final part of this work focused on development of novel tracers for A147T-TSPO variant. Using a combination of molecular modelling, MD simulations, and structure-guided drug design, I have evaluated plausible binding modes of established TSPO ligands to A147TTSPO. Results explain the origins of diminished affinity of some established TSPO ligands to A147T-TSPO. Moreover, I have identified the position of fluorine atom, which is a derivative of DPA-714 compound to bind to A147T-TSPO with sub-nanomolar affinity. The compound, denoted as MKD, is feasible for the radiosynthesis.