Short chain fatty acids (SCFAs) are postulated to modulate the immune development of neonates via epigenetic regulations such as histone deacetylase (HDAC) inhibition. In the context of atopic diseases, the inhibition of HDAC maintains T-cell homeostasis and induces naïve T-cell differentiation into adaptive Treg, which regulates the production of anti-inflammatory cytokines and suppression of Th2 immune responses.
Structure-based Ligand Discovery and Design
Major Facilitator Superfamily Domain containing 2A (Mfsd2a) was recently characterized as a sodium-dependent lysophosphatidylcholine (LPC) transporter expressed at the blood-brain barrier endothelium. It is the primary route for importation of docosohexaenoic acid and other long-chain fatty acids into foetal and adult brain, and is essential for mouse and human brain growth and function. Remarkably, Mfsd2a is the first identified MFS family member that uniquely transports lipids, implying that Mfsd2a harbours unique structural features and transport mechanism.
Finding small molecules that target allosteric sites remains a grand challenge for ligand discovery. In the protein kinase field, only a handful of highly selective allosteric modulators have been found. Thus, more general methods are needed to discover allosteric modulators for additional kinases. Here, we use virtual screening against an ensemble of both crystal structures and comparative models to identify ligands for an allosteric peptide-binding site on the protein kinase PDK1 (the PIF pocket).