Structure-Based Library Design and Fragment Screening for the Identification of Reversible Complement Factor D Protease Inhibitors

Chronic dysregulation of alternative
complement pathway activation
has been associated with diverse clinical disorders including age-related
macular degeneration and paroxysmal nocturnal hemoglobinurea. Factor
D is a trypsin-like serine protease with a narrow specificity for
arginine in the P1 position, which catalyzes the first enzymatic reaction
of the amplification loop of the alternative pathway. In this article,
we describe two hit finding approaches leading to the discovery of
new chemical matter for this pivotal protease of the complement system: in silico active site mapping for hot spot identification
to guide rational structure-based design and NMR screening of focused
and diverse fragment libraries. The wealth of information gathered
by these complementary approaches enabled the identification of ligands
binding to different subpockets of the latent Factor D conformation
and was instrumental for understanding the binding requirements for
the generation of the first known potent noncovalent reversible Factor
D inhibitors.