Evaluating interaction of pharmacologically potent organoselenides with transport protein human serum albumin: Spectroscopic and molecular dynamic simulations based mechanistic insights.

Organoselenides exhibit a wide range of biological functions; however, their interactions with major proteins remain poorly understood, with existing studies largely focused on cellular systems. To advance more potent selenium derivatives, a comprehensive understanding of the intermolecular forces governing their binding is essential for rational drug design. Here a series of six organoselenides with potential as therapeutic agents was investigated for its binding with human serum albumin (HSA) a chief protein in the distribution, transport, and bioavailability of therapeutic agents in the bloodstream. Spectroscopy, calorimetry and in silico studies were used to elucidate their binding affinity, binding site, and interaction mechanisms. Fluorescence quenching analysis revealed that 2,2'-diselanediyldinicotinamide (Se1), 1,2-diphenyldiselane (Se2), 2,2'-diselanediyldinicotinic acid (Se3) and 1,2-di(pyridin-2-yl)diselane (Se4) binds to HSA with moderate affinity, whereas 3,3'-diselanediyldipropionic acid (Se5) and (3S,4S)-tetrahydroselenophene-3,4-diol (Se6) exhibited negligible binding. Displacement studies using warfarin and ibuprofen in addition to docking studies indicated that none of the ligands bind to either Sudlow site I or site II. However, ligands Se1, Se2, and Se4 occupy the fatty acid binding site FA6, FA1 and FA5. Se3 binds to the cavity formed by the loop regions of subdomain IIIA and IIIB which is a non-conventional binding site. Circular dichroism and thermal melting measurements showed minimal perturbation of the structure of HSA upon ligand binding. These findings highlight distinct binding modes of organoselenides with HSA and provide important insights that may aid in the rational design of selenium-based therapeutics with improved pharmacokinetic properties.