A rational search for discovering potential neutraligands of human complement fragment 5a (hC5a)

The human complement fragment 5a ((h)C5a) is an extremely potent proinflammatory glycoprotein, which upon binding to C5aR triggers a plethora of immune and non-immunological responses in humans. Dysregulation of complement system is associated with the upregulation of (h)C5a, leading to the surge of proinflammatory cytokines, which further exacerbate the chronic inflammation induced pathological conditions. Thus, (h)C5a is considered as a major pharmacological target for developing complement therapeutics that can directly or indirectly modulate the function of (h)C5a. However, the idea of small molecules, directly neutralizing the function of excessive (h)C5a remains unexplored in the literature. By recruiting cheminformatics approach, the avenue of drug repositioning is explored in the current study for discovering novel neutraligands of (h)C5a. The systematic exercise yields a pool of potential neutraligands, from which four FDA approved drugs, such as carprofen, oxaprozin, sulindac and raloxifene have been subjected to a battery of computational and biophysical studies against (h)C5a. The data obtained from docking, molecular dynamics, and molecular mechanics Poisson-Boltzmann surface area studies, strongly correlate with the data obtained from the circular dichroism, steady state fluorescence, and fluorescence quenching studies, involving the recombinant (h)C5a and the selected drugs. The proof of the concept study successfully documents the rational discovery of first generation template neutraligands of (h)C5a through drug repositioning approach and suggests that the selected drugs perhaps bind functionally distinct hot spots on (h)C5a. The identified neutraligands can be subsequently optimized as complement specific therapeutics for strongly modulating the (h)C5a-C5aR signaling axes.