Polypharmacology or Promiscuity? Structural Interactions of Resveratrol With Its Bandwagon of Targets

Abstract

Resveratrol (3, 4', 5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and has long been thought to be the answer to the "French Paradox." There is no shortage of preclinical and clinical studies investigating the broad therapeutic activity of resveratrol. However, in spite of many comprehensive reviews published on the bioactivity of resveratrol, there has yet to be a report focused on the variety and complexity of its structural binding properties, and its multi-targeted role. An improved understanding of disease mechanisms at the systems level has enabled targeted polypharmacology to mature into a rational drug discovery approach. Unlike traditional hit-to-lead campaigns that typically optimize activity and selectivity for a single target, polypharmacological drugs aim to selectively target multiple proteins, while avoiding critical off target interactions. This strategy bears promise of improved efficacy and reduced clinical attrition. This review seeks to investigate whether the bioactivity of resveratrol is due to a polypharmacological effect or promiscuity of the phenolic small molecule by examining the modes of binding with its diverse collection of protein targets. We focused on annotated targets, identified via the ChEMBL database, and matched these targets to a representative structure deposited in the Protein Data Bank (PDB), as crystal structures are most informative in understanding modes of binding at the atomic level. We discuss the structural aspects of resveratrol itself that permits binding to multiple proteins in various signaling pathways. Furthermore, we suggest that resveratrol's bioactivity is a result of scaffold promiscuity rather than polypharmacology, and the variety of binding modes across targets display little similarity in the pattern of target interaction.

Keywords: polypharmacology; protein targets; receptor; repurposing; resveratrol.

FIGURE 1

(A) Three-dimensional chemical structure of resveratrol. Carbon (black), oxygen (red) and hydrogen (cyan). The two chemical moieties are shown as marked. (Image created by Discovery Studio Visualizer 4.5, Accelrys). (B) Two-dimensional chemical structure of resveratrol.

FIGURE 2

(A) Phylogenetic analysis of resveratrol co-crystal structures. The analysis clearly shows that there is no similarity in the resveratrol targets. Image produced by Phylogeny.fr server (http://www.phylogeny.fr/index.cgi) (Dereeper et al., 2008). (B) Resveratrol binding sites based on 15 resveratrol co-crystal structure chains corresponding to Table 1. Binding sites were generated by the TIP platform, Eidogen Sertanty Inc. (Hambly et al., 2006). There is no significant observed (above threshold) similarity among any of the resveratrol binding sites. Proteins shown: Leukotriene A4 hydrolase (3FTS), Phospholipase A2 (4QER), ATP synthase subunit alpha (2JIZ), Sulfotransferase family cytosolic 1B member 1 (3CKL), NRH dehydrogenase (quinone) 2 (1SG0), Peroxisome proliferator-activated receptor gamma (4JAZ), Transthyretin (5CR1), Troponin C (2I98), NAD-dependent protein deacetylase sirtuin-5 (4HDA), Tyrosine-tRNA ligase (4Q93), Myosin-2 heavy chain (3MNQ), Methionine adenosyltransferase subunit beta (2YDX), Estrogen receptor (4PP6), NAD-dependent protein deacetylase sirtuin-1(5BTR).

FIGURE 3

2D representations of co-crystallized resveratrol-target interactions. Image created via Ligand Interactions Viewer in the Schrodinger Maestro Suite 2017. All protein PDB structures were prepared using the Protein Preparation Wizard where likely protonation states of residues and ligand at physiological pH were generated. Green solid lines represent hydrophobic interactions, solid lines from the aromatic to other aromatic residues represent pi-stacking interactions, and solid arrows display hydrogen bonding interactions (https://www.schrodinger.com/).

FIGURE 4

Secondary structure representations of binary complexes. Secondary structures of the resveratrol-binding residues are shown as green colored ribbons, the remaining protein residues are shown in cornflower blue ribbons and the bound resveratrol is shown as orange colored sticks. The figure shows bound resveratrol in (A) Transthyretin, TTR (PDB: 5CR1); (B) Troponin C, cTnC (PDB: 2L98); (C) Myosin-2 heavy chain myosin-2 motor domain (PDB: 3MNQ); and (D) Tyrosine-tRNA ligase, TyrRS (PDB: 4Q93) binding sites. The non-conserved mode of secondary structure elements in the receptor binding site is evident. It should be noted that the secondary structure representation is according to Chimera classification. (Image created by Chimera).

FIGURE 5

Surface representation of binary complexes. The receptors are shown as surface representation (red color) and the bound resveratrol is shown as CPK (green color). The figure above shows bound resveratrol in prototype complexes for each function: (A) Leukotriene A4 hydrolase, LTA4H (PDB: 3FTS), inhibitory; (B) Estrogen receptor, ERα (PDB:4PP6) modulatory; (C) NAD-dependent protein deacetylase sirtuin-1, Sirt1 (PDB: 5BTR), activatory; (D) Transthyretin, TTR (PDB: 5CR1), Inhibitory. The above figures highlights resveratrol’s dissimilar binding modes among different and also similar targets; including deep and shallow (surface) binding pockets.