Comparative quantum chemical analysis of dexamethasone and hydrocortisone: electronic structure, and reactivity indices using DFT

Abstract

Context

The biological activity of steroidal compounds such as dexamethasone (DX) and hydrocortisone (HC) is closely linked to subtle variations in their molecular structure and electronic properties. This study provides a comparative quantum chemical analysis of DX and HC to clarify how these differences influence hydrogen bonding strength, reactivity, and their potential interactions with the glucocorticoid receptor (GR). Optimized geometries, natural bond orbital (NBO) analyses, frontier molecular orbitals (FMO), global reactivity descriptors, and average local ionization energy (ALIE) calculations demonstrate that DX exhibits greater polarity and electrophilic character compared to HC. These differences help explain the stronger receptor binding affinity observed for DX. Indeed, notably, despite the inherent limitations of gas-phase DFT calculations compared to experimental X-ray data, the theoretical results exhibit good agreement with experimental observations, suggesting the reliability of the computational approach in predicting molecular interactions within the GR active site.

Methods

All quantum chemical calculations were performed using density functional theory (DFT) with the B3LYP functional and 6-311++G(d,p) basis set. Structural optimization, FMO analysis, global reactivity descriptors, and dipole moment evaluations were carried out in Gaussian 09. NBO analysis was performed with NBO 5.0. Average local ionization energy (ALIE) surfaces were generated using Multiwfn 3.8, and molecular visualizations were produced with GaussView 5.0.