Study of clopidogrel and clonidine interactions for cardiovascular formulation: Progress from DFT modeling

Abstract

Clopidogrel and clonidine drugs are frequently used to treat cardiovascular illnesses 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, the band-gap energy, chemical potential, chemical hardness and softness parameters are calculated by 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 complement the analysis. Clonidine presents greater sensitivity to electrophilic attack, while, the electronic affinity is little higher for clopidogrel. Negative charge density is located in oxygen atoms of clopidogrel and positive charge is placed in nitrogens of clonidine, according to MEP map. The frontier orbital plots also confirm this finding. On the other hand, the drugs present similar reactivity in water. Clopidogrel is lesser reactive than clonidine, and the interaction between the molecules is taken place by physisorption, in agreement with TDOS plot. NBO analysis reveals a low charge variation in accordance with the physical adsorption-like bonding between the drugs. The lowest energy for clopidogrel-clonidine interaction is reached by the formation of four H bonds that is observed in IR spectrum by a significant intensity peak at 3360 cm-1. Hydrogen-bonds play a crucial role for controlled drug delivery application as it allows moderate and reversible drug adsorption, facilitating its release in the biological environment. IR spectra also support the absence of degradation or chemical reaction between the drugs confirming the preservation of the active pharmaceutical individual ingredient.