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

The human complement fragment 5a (^hC5a) 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 ^hC5a, leading to the surge of proinflammatory cytokines, which further exacerbate the chronic inflammation induced pathological conditions. Thus, ^hC5a is considered as a major pharmacological target for developing complement therapeutics that can directly or indirectly modulate the function of ^hC5a. However, the idea of small molecules, directly neutralizing the function of excessive ^hC5a 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 ^hC5a. 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 ^hC5a. 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 ^hC5a and the selected drugs. The proof of the concept study successfully documents the rational discovery of first generation template neutraligands of ^hC5a through drug repositioning approach and suggests that the selected drugs perhaps bind functionally distinct hot spots on ^hC5a. The identified neutraligands can be subsequently optimized as complement specific therapeutics for strongly modulating the ^hC5a-C5aR signaling axes.