Study of clopidogrel and clonidine interactions for cardiovascular formulations: progress from DFT modeling

Abstract

The drugs clopidogrel and clonidine are frequently used to treat cardiovascular diseases, which are the leading cause of mortality worldwide. Since these medications are frequently taken in combination, it is crucial to examine their molecular interactions. Therefore, herein, the bandgap energy, chemical potential, chemical hardness and softness parameters were calculated using a density functional theory (DFT)-based method. In addition, infrared (IR) spectrum, natural bond orbital (NBO), molecular electrostatic potential (MEP), electron localization function (ELF) and total density of states (TDOS) plots complemented the analysis. Clonidine exhibited greater sensitivity to electrophilic attack, while the electronic affinity of clopidogrel was slightly higher. According to the MEP map, negative charge density was located on the oxygen atoms of clopidogrel, and the positive charge was located on the nitrogen atoms of clonidine. Notably, both the drugs exhibited similar reactivity in water. Clopidogrel was less reactive than clonidine, and the interaction between the molecules occurred via physisorption, which was in agreement with the TDOS plot. NBO analysis revealed a low charge variation, in accordance with the physical adsorption-like bonding between the drugs. The lowest energy for the clopidogrel–clonidine interaction was attained via the formation of four H bonds, as indicated by a significant intensive peak at 3360 cm⁻¹ in the IR spectrum. Hydrogen bonds played a crucial role in the controlled drug delivery application as it allowed moderate and reversible drug adsorption, facilitating drug release in the biological environment. IR spectra also supported the absence of degradation or chemical reaction between the drugs, confirming the preservation of the individual active pharmaceutical ingredient.