In-silico evaluation of carbohydrate–lectin interactions : bridging oligosaccharides and glycomimetics

Carbohydrates play a vital role in a variety of physiological and pathological processes and, hence, represent an exciting class of molecules for the development of new therapeutic approaches.
However, carbohydrates have disadvantages such as high polarity, low absorption, and mostly weak binding affinities, which are unfamiliar to common marketed drugs. Yet, the strengths of carbohydrates and carbohydrate binding-sites are their specificity, as well as a high solubility. In manuscript 2: «What contributes to an effective mannose recognition domain?», we investigated how nature circumvents the drawbacks of carbohydrates and creates selective, high-affinity binding sites. To mitigate the carbohydrate’s drawbacks, while simultaneously retaining their strengths for therapeutic application, it is necessary to investigate the interactions of carbohydrates and lectins first. From manuscript 3: «The price of flexibility — A case study on septanoses as pyranose mimetics» and manuscript 4: «High-affinity carbohydrate-lectin interactions: How nature makes it possible», it quickly becomes apparent that hydrogen-bonds are the primary driving force of carbohydrate–lectin interactions and that they deserve particular attention. However, to successfully interpret hydrogen-bond networks of carbohydrate–lectin interactions and the design of carbohydrate-based drugs it is essential to work on the right target conformation. In manuscript 5: «Urinary tract infection — Which conformation of the bacterial lectin FimH is therapeutically relevant?» and manuscript 6: «E-selectin ligand complexes adopt an extended high-affinity conformation», we reported on conformational changes upon binding of a carbohydrate ligand, that led to a high-affinity state of the lectin.
With the gained insight, we developed Acca-Bruca, a software to assists medicinal chemists in decision-making on how to modify carbohydrates to overcome their inherent disadvantages. Acca-Bruca is described in manuscript 1: «Bridging oligosaccharides and glycomimetics with protein receptors — Acca-Bruca, an in-silico tool to categorize carbohydrate–lectin hydrogen bond interactions».