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Human C5a ( h C5a), one of the pro-inflammatory glycoproteins of the complement system is known to undergo production hyperdrive in response to stress and infection.  h C5a has been associated with the pathogenesis of many chronic and acute diseases, due to its proven ability in triggering the ‘cytokine storm’, by binding to its cognate receptor C5aR, expressed in myriad of tissues. Given the pleiotropic downstream function of  h C5a, it is logical to consider the  h C5a or its precursors as potential drug targets, and thus, we have been rationally pursuing the idea of neutralizing the harmful effect of excessive  h C5a, by implementing the repurposing strategies for FDA-approved drugs. Indeed, the proof of principle biophysical studies published recently is encouraging, which strongly supports the potential of this strategy. Considering BSA-carprofen as a reference model system, the current study further explores the inherent conformational plasticity of  h C5a and its effect in accommodating more than one drug molecule cooperatively at multiple sites. The data generated by recruiting a battery of experimental and computational biology techniques strongly suggest that  h C5a can sequentially accommodate more than one raloxifene molecule with an estimated Ki ∼ 0.5 µM and Ki ∼ 3.58 µM on its surface at non-analogous sites. The study hints at exploration of polypharmacology approach, as a new avenue for discovering synergistic drug molecule pairs, or drug molecules with ‘broad-range’ binding affinity for targeting the different ‘hot spots’ on  h C5a, as an alternative combination therapy for possible management of the ‘cytokine storm’-related inflammatory diseases, like COVID19. Communicated by Ramaswamy H. Sarma

Binding of raloxifene to human complement fragment 5a ( h C5a): a perspective on cytokine storm and COVID19