Multiscale Computational Insights into the Electronic Structure and V2 Receptor Binding of Tolvaptan

Abstract

Tolvaptan was investigated using an experimentally anchored multiscale computational workflow integrating density functional theory (DFT), time-dependent DFT, molecular docking, membrane molecular dynamics (MD), MM/GBSA, and ADMET prediction. B3LYP/6-311++G(d,p) calculations gave a HOMO–LUMO gap of 2.71 eV and an electrophilicity index of 17.46 eV, while natural bond orbital analysis identified n→π stabilization energies up to 260.0 kJ mol⁻¹. Among the tested TD-DFT models, B3LYP/SMD yielded the calculated λmax closest to the literature-reported methanolic absorption maximum. Re-docking of co-resolved R-tolvaptan into the vasopressin V2 receptor (PDB 9HAP) reproduced the experimental pose with a heavy-atom RMSD of 0.238 Å. AutoDock Vina scores were −8.34 and −8.31 kcal mol⁻¹ for R- and S-tolvaptan, respectively, indicating minimal static score separation. During independent 100-ns membrane MD simulations, both stereoisomers remained associated with the orthosteric pocket, whereas R-tolvaptan showed lower ligand RMSD and RMSF. Mean MM/GBSA estimates were −92.38 ± 6.69 and −81.83 ± 7.69 kcal mol⁻¹ for R and S, respectively. ADMET analysis predicted 93.24% intestinal absorption and a moderate hepatotoxicity risk. The study provides an experimentally referenced cross-scale framework for Tolvaptan and indicates stereochemistry-dependent differences in dynamic accommodation and calculated energetics without establishing experimental V2R enantioselectivity.