The research combine X-ray crystallography, computational chemistry, organic synthesis, and biological evaluation. We focus on two separate projects, involving the proteins positive regulatory factor A (PrfA) and Transthyretin (TTR).
To address the issue of increasing antibiotic resistance, drugs that inhibit the virulence of bacteria without killing them are important alternatives. PrfA is a virulence regulator of the bacterial pathogen Listeria monocytogenes causing listeriosis. We have previously identified small organic molecules that bind to PrfA, thus reducing the expression of virulence proteins. We have determined the X-ray crystal structures of some of these compounds in complex with PrfA, revealing that they can bind to different sites of the protein. Molecular dynamics (MD) simulations will be used to study the dynamics of different complexes, to further investigate properties important for binding to the different sites of PrfA, as well as requirements for virulence inhibition. The results will aid design and synthesis of compounds with improved in vivo properties.
Amyloidosis is a medical condition caused by the misfolding of proteins, resulting in formation of non-soluble fibrils that accumulate in different organs. We focus on the human plasma protein TTR involved in hormone transportation. Point mutations of TTR lead to dissociation of the native tetrameric form into monomers, resulting in fibril formation and amyloidosis. Through a fragment screen and screening of the Prestwick Chemical Library we have identified compounds that stabilize the tetrameric form of the protein, thus preventing amyloidosis. The impact of different point mutations on the dynamics and stability of TTR in complex with the identified stabilizers will be investigated using MD simulations, to define properties essential for stabilization as well as investigate the reasons for instability. The results will aid future design of compounds with improved TTR stabilization properties.