CD, UV, and In Silico Insights on the Effect of 1,3-Bis(1′-uracilyl)-2-propanone on Serum Albumin Structure

1,3-diaryl-2-propanone derivatives are synthetic compounds used as building blocks for the realization not only of antimicrobial drugs but also of new nanomaterials thanks to their ability to self-assemble in solution and interact with nucleopeptides. However, their ability to interact with proteins is a scarcely investigated theme considering the therapeutic importance that 1,3-diaryl-2-propanones could have in the modulation of protein-driven processes. Within this scope, we investigated the protein binding ability of 1,3-bis(1′-uracilyl)-2-propanone, which was previously synthesized in our laboratory utilizing a Dakin–West reaction and herein indicated as U2O, using bovine serum albumin (BSA) as the model protein. Through circular dichroism (CD) and UV spectroscopy, we demonstrated that the compound, but not the similar thymine derivative T2O, was able to alter the secondary structure of the serum albumin leading to significant consequences in terms of BSA structure with respect to the unbound protein (Δ(β-turn) + Δ(β-sheet) = +23.6%, Δ(α) = −16.7%) as revealed in our CD binding studies. Moreover, molecular docking studies suggested that U2O is preferentially housed in the domain IIIB of the protein, and its affinity for the albumin is higher than that of the reference ligand HA 14−1 (HDOCK score (top 1–3 poses): −157.11 ± 1.38 (U2O); −129.80 ± 6.92 (HA 14−1); binding energy: −7.6 kcal/mol (U2O); −5.9 kcal/mol (HA 14−1)) and T2O (HDOCK score (top 1–3 poses): −149.93 ± 2.35; binding energy: −7.0 kcal/mol). Overall, the above findings suggest the ability of 1,3-bis(1′-uracilyl)-2-propanone to bind serum albumins and the observed reduction of the α-helix structure with the concomitant increase in the β-structure are consistent with a partial protein destabilization due to the interaction with U2O.