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 re- search interest due to its role in various pathologies, including cancer, tuberculosis, and sclerosis. However, excessive calcitriol levels or heightened sensitivity of the vitamin D receptor (VDR) to this compound can lead to hypercalcemia. Consequently, there is intense interest in developing calcitriol analogues that maintain effective interaction with the VDR, exhibiting comparable or enhanced biological activity without inducing hypercalcemia. Understanding the molecular interactions between calcitriol and the VDR is therefore critical for the rational design of novel analogues. In this study, we employed the ONIOM hybrid methodology, which combines different computational levels for distinct regions of the system, to investigate the interactions between cal- citriol and the VDR active site while reducing computational cost without sacrificing accuracy. Specifically, the ONIOM2(B3LYP/6-31++G(2d,p):PM7) approach was used to characterize the binding interactions of the active vitamin D metabolite within the receptor’s active site. Additionally, TD-DFT calculations were performed to explore the electronic properties and potential influences of intermolecular interactions on the calcitriol-residue complex. We analyzed conformational and energetic aspects of the VDR-calcitriol interaction, including charge transfer phenomena and the UV-Visible absorption spectrum arising from interactions with amino acid residues. This com- prehensive computational study of the interactions and electronic transitions between calcitriol and VDR amino acid residues provides valuable insights that may guide the development of new calcitriol analogues with improved therapeutic profiles, particularly in the absence of experimental structural data.