Ab initio and DFT investigation of the mechanism and hydration pattern of sialidase and its inhibitors

Abstract

Functional and structural information about sialidase enzyme is vital in the discovery of sialidase inhibitors. Hence this study investigates the catalytic mechanism of sialidase enzyme by first principle calculations and it demonstrates that the enzyme mechanism proceeds via the formation of an oxocarbocation intermediate and not by covalent intermediate. This will facilitate the design and development of sialidase antiviral inhibitors. The ability to engineer water binding sites in the interface between a drug and its receptor might prove useful in drug design. Therefore, this study has employed RHF/6-31G and DFT RB3LYP/6-31G(d) levels of theory to explore the hydration pattern of sialyate and sialidase inhibitors with up to seven water molecules. The results show that the solvation free energy increases as a function of water molecules and ligand binding energy of the compounds progressively decreases as a function of water molecules. It reveals that carboxylate oxygen, hydroxyl, amino, methoxy group and glycerol side chains were the strong water binding sites in the ligand-receptor interactions. Substituents have also been introduced at the various positions around functional site of sialidase inhibitors to evaluate their binding affinity. We found that methoxy, methyl, and amino groups were the promising substituents with higher binding affinity and it will aid in the design and development of potential sialidase antiviral inhibitors in the near future.