The synthesis and functionalization of carbohydrate derivatives play pivotal roles in advancing drug discovery and therapeutic development. Methyl-α-D-glucopyranoside (MGP) and its six derivatives have been selected for use as computational tools for drug discovery in medicinal chemistry. The structural and thermodynamic properties of the derivatives were optimized via density functional theory (DFT) with B3LYP/3-21G level theory. The subsequent analysis also examined the electronic energies, enthalpies, Gibbs free energies, heat capacity, entropy, HOMO‒LUMO gaps, density of states and molecular electrostatic potential (MEP) of these modified compounds. Molecular docking analysis was performed on these compounds with the targeted protein monkeypox virus (MPXV) to investigate their binding affinity and molecular interaction. Amino acid residues such as ARG127, ARG119, ASP10, ASP123, ASN78, THR120, HIS100, ARG129, ASN14, LYS16, GLU77, etc. have various binding affinities with ligands via hydrogen bonding and other nonbonding interactions. Although the parent compound successfully showed good findings, the derivatives of the compounds also presented improved pharmacokinetic properties, as shown by ADMET analysis. The collective findings from these studies suggest that MGP derivatives exhibit promising bioactive potential and could serve as effective targets for our proteins of interest.