Role of Non‐Covalent Forces in Ferulic Acid–Gliclazide Complex Formation: A DFT Study

Abstract Gliclazide (GIL) is a potent drug for the treatment of type 2 diabetes, interacted with a phytochemical, ferulic acid (FER), with the help of density functional theory. The investigation on the geometry and vibration of the complexation confirmed the occurrence of a strong non‐covalent interaction between the carboxylic, hydroxyl, and amine groups of the GIL and FER, respectively. The structural analysis predicted three interaction patterns: FG1, FG2, and FG3, among which the FG3 geometry had the highest E Int of −41.22 kcal/mol. The bond strength of the interacting groups was obtained through QTAIM, the FG3 configuration was found with > 0 and H (r) < 0 and E HBE of −12.71 and −7.95 kcal/mol indicating the presence of a strong non‐covalent interaction. The HOMO and LUMO orbitals of FG3 experienced a stabilization, resulting in a reduction of E g from 4.94 and 4.10 eV to 4.05 eV. The reduction in the HOMO–LUMO gap in turn increased the charge transfers between the herb and drug with E (2) of 11.17 and 13.64 kJ/mol. The stability of the FER‐GIL complexation was tested with the help of ADMP at 300 and 320 K. The complex had minimal fluctuations of 13.33 and 21.32% of the bonds in their interaction site while maintaining structural integrity and could possibly modulate the pharmacokinetic properties, making it a promising candidate for hybrid drug strategies in type 2 diabetes treatment.