Curcuminoids as inhibitors of thioredoxin reductase: A receptor based pharmacophore study with distance mapping of the active site

Curcumin is the yellow pigment of turmeric that interacts irreversibly forming an adduct with thioredoxin reductase (TrxR), an enzymeresponsible for redox control of cell and defence against oxidative stress. Docking at both the active sites of TrxR was performed to comparethe potency of three naturally occurring curcuminoids, namely curcumin, demethoxy curcumin and bis-demethoxy curcumin. Results showthat active sites of TrxR occur at the junction of E and F chains. Volume and area of both cavities is predicted. It has been concluded bydistance mapping of the most active conformations that Se atom of catalytic residue SeCYS498, is at a distance of 3.56 from C13 ofdemethoxy curcumin at the E chain active site, whereas C13 carbon atom forms adduct with Se atom of SeCys 498. We report that at leastone methoxy group in curcuminoids is necessary for interation with catalytic residues of thioredoxin. Pharmacophore of both active sites ofthe TrxR receptor for curcumin and demethoxy curcumin molecules has been drawn and proposed for design and synthesis of most probablepotent antiproliferative synthetic drugs.