Molecular speciation effect on docking and drug design: a computational study for mangiferin, a carbohydrate-polyphenol bioconjugate as a test case

Abstract

A study to evaluate the effect of molecular speciation considering methodologies to assign partial charges and conformational search processes for a docking test was made with mangiferin (MGF). This compound was selected as a model to explore speciation effects on drug design due to the speciation studies previously performed, and because it is a bioconjugate containing carbohydrate and polyphenolic xanthonoid groups, both moieties important as potential-drug candidates. PEOE (Partial Equalization of Orbital Electronegativity) resulted the best method to assign partial charges, with a good compromiso between precision and computational cost, among different Classical Molecular Force Fields and Quantum Mechanics methods that were compared with Density Functional Theory calculations as the reference methodology. The number of conformations in energy minima showed to be extremely dependent upon partial charge assignation, as well as their geometry. In docking simulations of MGF on albumin drug-site 1, it was showed the relevance of choosing the properly expected chemical species for the pH value of interest since neutral MGF or deprotonated at the hydroxyl group on position 1 results in orientations significantly different from those predicted for the species deprotonated at the hydroxyl group on position 6, which is the predominant deprotonation site in accordance with the speciation study. The first two species present a tendency to expose the carbohydrate region to solvent occupying the same region in the binding site, while the molecule deprotonated in position 6 exhibits a preference for a different region of the site with its xanthonoid moiety exposed. Carbohydrate-polyphenol bioconjugates, such as MGF combine two types of bioactive molecules being both important as leaders for drug design.