Mechanistic insights into inhibition of CCL2-guided leukocyte recruitment by oxyresveratrol and its derivatives

Inflammatory responses are the outcomes of coordinated interactions amongst chemokines and their exclusive non-negotiable counterparts such as glycosaminoglycans and GPCRs. CCL2 in conjunction with other immune molecules positively regulates the migration, infiltration, and recruitment of macrophages to the site of inflammation, hence is a promising target from pharmaceutical perspective. Stilbenes such as resveratrol and its derivatives are well documented for their anti-inflammatory responses. The current study presents a structure-based screening and unravels the molecular recognition patterns of stilbene derivatives against CCL2 chemokine to identify their potential to interact and inhibit the proinflammatory activity of CCL2. Structure based in silico screening of aglycosidic stilbenes followed by fluorescence, NMR and in vitro chemotaxis experiments established that oxyresveratrol (ORS), a symmetrical hydroxylated stilbene, prominently binds CCL2 and inhibits macrophage migration. Further, extensive computational analysis reveals the atom level details of molecular recognition events on ORS and its two derivatives ORS10/ORS16, whereby ORS16 demonstrated as a superior CCL2 binding counterpart. Indeed, NMR and computational analysis suggested that ORS interacts through the receptor binding site of CCL2 to attenuate the leukocyte migration. In brief, the current study provides a basis for designing potential inhibitors opting ORS, and more precisely ORS16 as a primary architecture for targeting CCL2-mediated inflammatory proceedings.