N-Methylation has a significant impact on improving oral bioavailability, lipophilicity and aqueous solubility of peptide-based lead drug structures. The selected mono-amino acid derivatives Ac-X-OMe, where X= Gly, Val, Leu, Ile, Phe, Met, Cys, Ser, Asp and His as well as their corresponding N-methylated analogues were studied. The ClogP values of all N-methylated examples are greater than native compounds. Quantum chemical calculations were performed to estimate the aqueous solubility of these lipophilic compounds using density functional theory (DFT) with B3LYP density functional. To confirm the contribution of dispersion forces on quantum chemical data, the long-range corrected (LC) hybrid density functional (ωB97X-D) was also probed for some amino acid derivatives. The ωB97X functional gave similar results. Our results reveal that after mono N-methylation of the peptide backbone, ΔGsolv becomes more negative (more water soluble) while polarizability, dipole moment are also increased. NBO atomic charges for the amide N, C and O nuclei become more positive/(less negative) after N-methylation. All N-methylated amino acids have higher EHOMO (less negative) in comparison to the amino acid analogues, and in all cases N-methylation decreases EHOMO-LUMO. The calculated amide cis/trans activation energy (EA) of all the N-methylated amino acid derivatives was lower than native species. N-methylation of these compounds leads to an increase in lipophilicity, aqueous solubility, polarization, dipole moment and lowering of the cis/trans amide energy barrier (EA).