Density functional theory based probe of the affinity interaction of saccharide ligands with extra-cellular sialic acid residues

Abstract

Changes in glycosylation pattern leads to malignant transformations among the cells. In combination with upregulated actions of sialyltransferases, it ultimately leads to differential expression of sialic acid (SA) at cell surface. Given its negative charge and localization to extracellular domain, SA has been exploited for the development of targeted theranostics using approaches, such as, cationization and appending recognition saccharides on carrier surface. In this study, we have performed quantum mechanical calculations based on density functional theory (DFT) to study the interaction of saccharides with extracellular SA. Gradient-corrected DFT with the three parameter function (B3) was utilized for the calculation of Lee–Yang–Parr (LYP) correlation function. Atomic charge, vibrational frequencies and energy of the optimized structures were calculated through B3LYP. Our calculations demonstrate a stronger galactose–sialic acid interaction at tumour-relevant low pH and hyperthermic condition. These results support the application of pH responsive delivery vehicles and targeted hyperthermic chemotherapy for eradicating solid tumour deposits. These studies, conducted a priori, can guide the formulation scientists over appropriate choice of ligands and their applications in the design of ‘smart’ theranostic tools.

Keywords:

• cancer
• hypersialylation
• recognition saccharides
• density functional theory
• targeted theranostics

Abbreviations:

• SA, sialic acid
• DFT, density functional theory
• B3LYP, Becke 3-Parameter Lee, Yang and Parr
• CMAS, cytidine monophosphate N-acetylneuraminic acid synthase
• Gal, galactose
• Man, mannose
• PBA, phenylboronic acid
• DFT, density functional theory
• ASDase, aspartate semialdehyde dehydrogenase
• EcPLA₂, Echis carinatus Phospholipase A₂
• AChE, Acetylcholine Esterase
• BACE1, Beta-secretase 1
• CK2, casein kinase 2
• GSK3β, glycogen synthase kinase 3β
• BSSE, basis set superposition error
• FF, fukui function
• NBO, natural bond orbital
• HOMO, highest occupied molecular orbital
• LUMO, lowest unoccupied molecular orbital
• HLG, HOMO-LUMO gap
• MEP, molecular electrostatic potential
• NC, nanocarriers.