In pursuit of a novel UTI treatment strategy - an "in silico" study of the FimH adhesin

Carbohydrate-binding proteins (particularly lectins) are frequent targets of
present pharmaceutical research. While of high priority due to their involvement
in an array of pathophysiological events, these systems (along with their
saccharidic ligands) present many challenges related, in part, to the limited
means of their in-depth structural exploration. A foothold towards improving the
design throughput of carbohydrate-based drugs is provided by the
state-of-the-art in silico technologies, offering both means of structure
generation and refinement as well as rapid screening of putative ligands. In
this account, the application of some of these methods (docking, molecular
dynamics, and MM-GBSA/QSAR protocols), toward inhibiting FimH - a virulence
factor of urinary tract infections - is presented. The role of this bacterial
lectin involves the adhesion to highly-mannosylated urothelial cell surfaces.
This process is supported by the presence of urine flow, lead- ing to the
so-called catch-bonding characteristics. The presented work was focused
primarily on the rationalization and optimization of the binding of mannosidic
ligands with available crystallographic and in vitro data. As a result,
several series of new promising compounds were designed, with selected among
them synthesized, assayed, and published. In addition, an array of molecular
dynamics simulation techniques was employed to probe the structural properties
of the native, two-domain protein in presence and absence of shear conditions.
Through this, a receptor conformation was identified, that differed (including
the binding site) from ones previously employed in structure-based design
approaches. Given the wealth of data reporting the existence of FimH variants
with a broad range of affinities towards their natural ligands (further
dependent on many endogenic and exogenic factors), the reported discoveries may
lead to versatile and potent inhibitors, superior to currently applied
antibiotic treatments.