Virtual Screening of Chemical Compounds for Discovery of Complement C3 Ligands

The complement system is our first line of defense against foreign pathogens, but when it is not properly regulated, complement is implicated in the pathology of several autoimmune and inflammatory disorders. Compstatin is a peptidic complement inhibitor that acts by blocking the cleavage of complement protein C3 to the proinflammatory fragment C3a and opsonin fragment C3b. In this study, we aim to identify druglike small-molecule complement inhibitors with physicochemical, geometric, and binding properties similar to those of compstatin. We employed two approaches using various high-throughput virtual screening methods, which incorporate molecular dynamics (MD) simulations, pharmacophore model design, energy calculations, and molecular docking and scoring. We have generated a library of 274 chemical compounds with computationally predicted binding affinities for the compstatin binding site of C3. We have tested subsets of these chemical compounds experimentally for complement inhibitory activity, using h...