BPS2026 – Computational study of small molecules targeting complement protein 5 (C5) as potential treatment for inflamatory disorders

Inflammatory disorders are the leading cause of mortality in hospitals. Dysregulation of proteins involved in the inflammatory cascade are known to contribute to immune system dysfunction. The complement component 5 (C5) protein plays a major role in the terminal phase of the complement cascade, where its cleavage into C5a and C5b initiates an inflammatory response. Dysregulated activation of this cleavage has been implicated in the pathology of sepsis and other inflammatory disorders. Selective inhibition of C5 activation by preventing its proteolytic cleavage has demonstrated therapeutic potential in sepsis animal models. The Arg751-Leu752 peptide bond, accessible and solvent-exposed, enables convertase enzymes to cleave C5. The FDA has not yet approved molecule inhibitors; therefore C5 inhibition is of important clinical interest. This study aimed to identify novel small-molecule inhibitors of C5 cleavage using computational approaches. A library of ∼500,000 N-phenyl-N′-benzylurea derivatives - selected based on reports of urea scaffolds as complement pathway modulators—was screened through molecular docking with Dock6. We used a small-molecule inhibitor (IC 50 < 0.005 μM) previously characterized by Jenzda et al. as a positive control, which binds in the vicinity of the cleavage site but does not directly interact with residues Arg751 and Leu752, to validate docking performance and provide a baseline for binding affinity and stability. Top-scoring ligands and the control inhibitor were further analyzed with molecular dynamics simulations, binding free-energy calculations, and solvent accessibility analysis of the C5 binding site. Several ligands demonstrated stable binding affinities comparable to the control (−40.1 ± 0.1 kcal/mol). These findings provide a rational basis for downstream experimental validation and the development of targeted modulators of complement-mediated hyperinflammation in sepsis.