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Planta Med 2015; 81(06): 507-516
DOI: 10.1055/s-0035-1545910
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Discovery of the Glycogen Phosphorylase-Modulating Activity of a Resveratrol Glucoside by Using a Virtual Screening Protocol Optimized for Solvation Effects

Nikolaos Mavrokefalos
1   Division of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
,
Vassilios Myrianthopoulos
1   Division of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
,
Aikaterini S. Chajistamatiou
2   Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
,
Evangelia D. Chrysina
2   Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
,
Emmanuel Mikros
1   Division of Pharmaceutical Chemistry, School of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece
› Author Affiliations
Further Information

Publication History

received 06 July 2014
revised 26 February 2015

accepted 03 March 2015

Publication Date:
15 April 2015 (online)

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Abstract

The identification of natural products that can modulate blood glucose levels is of great interest as it can possibly facilitate the utilization of mild interventions such as herbal medicine or functional foods in the treatment of chronic diseases like diabetes. One of the established drug targets for antihyperglycemic therapy is glycogen phosphorylase. To evaluate the glycogen phosphorylase inhibitory properties of an in-house compound collection consisting to a large extent of natural products, a stepwise virtual and experimental screening protocol was devised and implemented. The fact that the active site of glycogen phosphorylase is highly hydrated emphasized that a methodological aspect needed to be efficiently addressed prior to an in silico evaluation of the compound collection. The effect of water molecules on docking calculations was regarded as a key parameter in terms of virtual screening protocol optimization. Statistical analysis of 125 structures of glycogen phosphorylase and solvent mapping focusing on the active site hydration motif in combination with a retrospective screening revealed the importance of a set of 29 crystallographic water molecules for achieving high enrichment as to the discrimination between active compounds and inactive decoys. The scaling of Van der Waals radii of system atoms had an additional effect on screening performance. Having optimized the in silico protocol, a prospective evaluation of the in-house compound collection derived a set of 18 top-ranked natural products that were subsequently evaluated in vitro for their activity as glycogen phosphorylase inhibitors. Two phenolic glucosides with glycogen phosphorylase-modulating activity were identified, whereas the most potent compound affording mid-micromolar inhibition was a glucosidic derivative of resveratrol, a stilbene well-known for its wide range of biological activities. Results show the possible phytotherapeutic and nutraceutical potential of products common in the Mediterranean countries, such as red wine and Vitis products in general or green raw salads and herbal preparations, where such compounds are abundant.

Key words

virtual screening - glycogen phosphorylase - solvation effects - hydration mapping - diabetes - docking-scoring - trans-resveratrol glucoside - tachioside
 

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