Buried Hydrogen Bond Interactions Contribute to the High Potency of Complement Factor D Inhibitors.

ABSTRACT: Aberrant activation of the complement system is associated with diseases, including paroxysmal nocturnal hemoglobinuria and age-related macular degeneration. Complement factor D is the rate-limiting enzyme for activating the alternative pathway in the complement system. Recent development led to a class of potent amide containing pyrrolidine derived factor D inhibitors. Here, we used biochemical enzymatic and biolayer interferometry assays to demonstrate that the amide group improves the inhibitor potency by more than 80-fold. Our crystal structures revealed buried hydrogen bond interactions are important. Molecular orbital analysis from quantum chemistry calculations dissects the chemical groups participating in these interactions. Free energy calculation supports the differential contrib

SUBMITTER: Yang CY 

PROVIDER: S-EPMC5151139 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature