Novel Complement Protein 5 Inhibitors as Candidate Therapies for Sepsis

Rhicha Rupakheti
Dr. Tim Humphry and Dr. Bill R. Miller (A.T. Still University), Faculty Mentors

Sepsis is a leading cause of mortality worldwide and is driven by dysregulated immune response that leads to inflammation and organ failure. The complement system, particularly the complement protein 5 (C5), plays a central role in the cascade. Cleavage of C5 at the R751–L752 peptide bond drives downstream inflammatory signaling, making inhibition of this cleavage promising therapeutic strategy. Currently, no inhibitor of C5 activation is approved for the treatment of sepsis. 

This project employed a computational de novo ligand design workflow using DOCK6 to generate 880 ligands. As a control, we utilized a small-molecule inhibitor (IC50 < 0.005 µM) from literature that binds in the vicinity of the cleavage site but does not directly interact with residues Arg751 and Leu752. Molecular dynamics (MD) simulations evaluated ligand binding stability and solvent accessibility. Preliminary results indicate several de novo candidates show comparable binding affinities and reduced solvent exposure at the cleavage site.

 

Keywords: Computational Chemistry, Protein, Molecular Dynamics, Sepsis, de novo , SASA, ligand

Topic(s):Biochemistry and Molecular Biology
Biology
Chemistry

Presentation Type: Oral Presentation

Session: TBA
Location: TBA
Time: TBA