Study of Calcitriol Interaction with the Vitamin D Receptor Using DFT and TD-DFT Calculations

Calcitriol, the primary active metabolite of vitamin D, has garnered significant research interest due to its role in several pathologies. However, excessive calcitriol levels or heightened sensitivity of the vitamin D receptor (VDR) can lead to hypercalcemia, motivating the search for analogues that preserve therapeutic activity while reducing adverse effects. Understanding the molecular basis of VDR-calcitriol recognition is therefore essential for rational ligand design. In this study, we applied the ONIOM2(B3LYP/6-31++G(2d,p):PM7) hybrid methodology to characterize VDR-calcitriol interactions and identify the most stable conformations while ensuring computational efficiency. Additionally, TD-DFT calculations were performed to explore its electronic properties. We show that calcitriol remains the dominant chromophore and that its main π → π* transition is subtly influenced by interactions with TRP286 and TYR295, providing residue-level insight that is experimentally inaccessible due to the absence of UV-vis data for the holo complex. Furthermore, the calculated binding energy (-11.88 kcal/mol) is consistent with the experimental affinity of the crystallographic VDR construct, supporting the reliability of the predicted binding mode. This integrated analysis of structural, energetic, and electronic features offers new mechanistic insight into VDR-calcitriol recognition and may guide the development of analogues with improved therapeutic profiles.