Pharmacokinetic Profiling, Molecular Docking, and Thermochemical Properties of Methyl α-D-Glucopyranoside Derivatives Through ADMET and DFT Approaches

Abstract

Carbohydrate derivatives, particularly monosaccharide derivatives, are of significant interest in carbohydrate chemistry due to their role in synthesizing biologically active compounds. Consequently, the chemistry, biochemistry, and microbiology of carbohydrate derivatives are essential in drug development and pharmaceutical research. Modification of hydroxyl (-OH) groups through acylation enhances their biological activity. In this research, we optimized methyl α-D-glucopyranoside (MαGP, 1), a monosaccharide molecule, and several of its acylated derivatives via density functional theory (DFT). All synthesized derivatives are optimized at the B3LYP/3-21G level of theory. The electronic energies, enthalpies, free energies, heat capacities, entropies, molar refractivity, polarizability, dipole moments, HOMO‒LUMO gaps, and molecular electrostatic potentials (MEPs) of these modified compounds were also investigated in the subsequent analysis. Most of the synthesized derivatives inhibited the gram-positive bacteria Bacillus susbtilis and the fungus Fusarium equisaties more strongly. In this study, we used a blinded molecular docking approach to identify potential inhibitors of the Bacillus subtilis Obg protein (PDB: 1LNZ) and Fusarium equisaties (PDB: 5AJH). Compound 4 had the highest binding affinity for the ILNZ protein (-7.0 kcal/mol), and compounds 5 and 6 had the highest binding affinity for the 5AJH protein (-7.2 and -7.1 kcal/mol, respectively). Some of the compounds investigated here could bind near crucial catalytic residues, Arg236 and Arg238, of the main protease, and the molecules were surrounded by other active site residues, such as Lys156, Pro91, and Glu333. Finally, ADMET analysis revealed that modified derivatives of methyl α-D-glucopyranoside are less toxic, as the oral rat acute toxicity (LD50) values of compounds 4 and 6 were 2.170 mg/kg and 2.080 mg/kg, the oral rat chronic toxicity (LOAEL) values of compounds 3, 4, and 5 were 1.524 mg/kg, 1.421 mg/kg, and 1.293 mg/kg, whereas the BBB permeability values of compounds 2 and 4 were -0.367 cm/s and -0.542 cm/s, respectively. Thus, these derivatives have improved pharmacokinetic features compared with those of the mother drug. The Chittagong Univ. J. Sci. 46(1): 101-125, 2025