Structure-based Ligand Discovery and Design

In Silico and in Vitro Interactions between Short Chain Fatty Acids and Human Histone Deacetylases

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.

type: 
Journal Paper
journal: 
Biochemistry, 2017, doi: 10.1021/acs.biochem.7b00508
Impact Factor: 
2.938

Structural insights into the transport mechanism of the human sodium-dependent lysophosphatidylcholine transporter Mfsd2a

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.

type: 
Journal Paper
journal: 
The Journal of Biological Chemistry 2016 Mar 4. pii: jbc.M116.721035
pubmed: 
26945070
Url: 
http://www.ncbi.nlm.nih.gov/pubmed/26945070
Impact Factor: 
4.57

Small-Molecule Allosteric Modulators of the Protein Kinase PDK1 from Structure-Based Docking

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).

type: 
Journal Paper
journal: 
Journal of Medicinal Chemistry, 2015, Oct 22, 58, Pg 8285-8291, doi: 10.1021/acs.jmedchem.5b01216
pubmed: 
26443011
Url: 
http://pubs.acs.org/doi/10.1021/acs.jmedchem.5b01216
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