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.
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Anna
0000-0002-3114-8679
A
Vulpetti
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Stefan
S
Randl
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Simon
S
Rüdisser
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Nils
N
Ostermann
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Paul
P
Erbel
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Aengus
A
Mac Sweeney
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Thomas
T
Zoller
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Bahaa
B
Salem
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Bernd
B
Gerhartz
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Frederic
F
Cumin
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Ulrich
U
Hommel
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Claudio
C
Dalvit
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Edwige
E
Lorthiois
Novartis Institutes for BioMedical Research, Novartis Pharma AG , Novartis Campus, CH-4056 Basel, Switzerland.
Jürgen
J
Maibaum
D020134:Catalytic Domain; D011416:Complement Factor D / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D011480:Protease Inhibitors; C493488:CFD protein, human; D011416:Complement Factor D