Discovery of Novel Potential Human Targets of Resveratrol by Inverse

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Discovery of Novel Potential Human Targets of Resveratrol by Inverse Molecular Docking Katarina Kores, Samo Lešnik, Urban Bren, Dusanka Janezic, and Janez Konc J. Chem. Inf. Model., Just Accepted Manuscript • DOI: 10.1021/acs.jcim.8b00981 • Publication Date (Web): 18 Mar 2019 Downloaded from http://pubs.acs.org on March 19, 2019

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Journal of Chemical Information and Modeling

Discovery of Novel Potential Human Targets of Resveratrol by Inverse Molecular Docking Katarina Koresa, Samo Lešnikb, Urban Brena,b,c, Dušanka Janežičc,*, Janez Koncb,c,* a University

of Maribor, Faculty for Chemistry and Chemical Technology Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia b

c

National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia

University of Primorska, Faculty of Mathematics, Natural Sciences and Information Technology, Glagoljaška 8, SI-6000 Koper, Slovenia

* Corresponding authors: Dušanka Janežič, University of Primorska, Faculty of Mathematics, Natural Sciences and Information Technologies, Glagoljaška 8, SI–6000 Koper, Slovenia, Tel: + 386 5 611 76 59, E–mail: [email protected]. Janez Konc, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia; University of Primorska, Faculty of Mathematics, Natural Sciences and Information Technologies, Glagoljaška 8, SI–6000 Koper, Slovenia, Tel: + 386 1 4760 273, E–mail: [email protected].

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Abstract Resveratrol is a polyphenol known for its antioxidant and anti-inflammatory properties which support its use as a treatment for variety of diseases. There are already known connections of resveratrol to chemoprevention of cancer due to its ability to prevent tumor initiation and inhibit tumor promotion and progression. Resveratrol is also believed to be important in cardiovascular diseases and neurological disorders, such as Alzheimer’s disease. Using an inverse molecular docking approach, we sought to find new potential targets of resveratrol. Docking of resveratrol into each ProBiS predicted binding site of >38,000 protein structures from the Protein Data Bank was examined and a number of novel potential targets into which resveratrol was docked successfully were found. These explain known actions or predict new effects of resveratrol. The results included three human proteins that are already known to bind resveratrol. A majority of proteins discovered however have no connections with resveratrol. We report new potential target human proteins and proteins connected with different organisms into which resveratrol can dock. Our results reveal previously unknown potential target human proteins, whose connection with cardiovascular and neurological diseases could lead to new potential treatments for variety of diseases. We believe that our research could help in future experimental studies on activity resveratrol in humans. Keywords: resveratrol, polyphenol, inverse molecular docking, ProBiS, anticarcinogenic effects


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Introduction Resveratrol (3,5,4’-trihydroxystilbene, Figure 1) is a natural secondary metabolite found in many plants such as grapes and peanuts, and also in several food products, including red wine and grape juice. Produced in response to plant disease, injury or stress, resveratrol has two geometric isomers, cis and trans, and its biological activity is mostly attributed to the latter.1,2 It was first isolated in 1940 from the roots of white hellebore (Veratrum grandiflorum O. Loes) and was first characterized as a phytoalexin3 while it can also be classified within the stilbene or the polyphenol group.4 It is mostly known due to its antioxidant and anti-inflammatory properties.5

Figure 1. Chemical structure of trans- (left) and cis-resveratrol (right). Multiple reports suggest that resveratrol can be used for prevention and treatment for a variety of diseases.4,6 Delmans et al4 explains the mechanism of the effects of resveratrol in cancer chemoprevention. Resveratrol can prevent tumor initiation by scavenging for free radicals that damage DNA. By activating detoxifying enzymes, it can modulate polyamine metabolism and so inhibit tumor promotion. It can also inhibit tumor progression by the modulation of the cell cycle and induction of apoptosis.4 In breast cancer, resveratrol can make tumor cells more susceptible to chemotherapy by metabolic remodeling and cell differentiation.7 Resveratrol is also thought to be important in conjunction with cardiovascular disorders including hypertension, heart failure and atherosclerosis.6,8 Research also suggest positive effects upon treatment of neurological disorders such as spinal muscular atrophy9,


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autism spectrum disorders10 and Alzheimer’s disease11 with resveratrol. Many other potential therapeutic uses of resveratrol are described in detail by Baur and Sinclair3. In its pure form, resveratrol is a fat-soluble molecule which is also soluble in ethanol (~200 mM). It is almost insoluble in water (~0.13 mM)12, but it exhibits high membrane permeability (logP = 3.1)13. Therapeutic applications of resveratrol are limited by its low bioavailability, which is the consequence of limited stability, high metabolism and poor water solubility. It is a very photosensitive compound, as light exposure causes trans-resveratrol to convert into cis-resveratrol.12 Resveratrol is rapidly metabolized, mainly into sulfo- and glucuronide forms, which are rapidly eliminated in the urine. In plasma, most of the trans-resveratrol as well as its metabolites are bound to lipoproteins. Following oral administration, the free form concentration of resveratrol is very low and can even be undetectable.14 Improvement of bioavailability has become an important part of resveratrol research. Studies vary from water-in-oil-in-water emulsions with trans-resveratrol15 as well as a soluble galenical form bound16 to chitosan coating and also liposome compositions17. Drug discovery is driven by the desire to identify ligands, whose modes of action are defined. Among the many computational methods for drug discovery we focused on the inverse molecular docking approach.18,19 Our aim was to find new potential targets of resveratrol using an inverse molecular docking approach, which refers to the procedure of docking a ligand to members of a library of protein structures.20 Inverse docking has been used successfully to discover new potential targets for small molecule drugs, natural products or other ligands.20–24 Grinter et al20 used the approach to identify new potential anticancer targets. Moreover, Chen and Zhi21 used the approach to identify new potential targets of the anticancer drug Tamoxifen. Inverse screening was also used by Madagi and Balekundri25 for identification of anti-prostate cancer targets of resveratrol. Inverse docking strategy needs a sufficient number of three-dimensional protein structures and a database of all binding sites from the


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protein database entries.21 Using the inverse docking method, we searched more than 38,000 proteins for the highest scoring poses of ligands in specified binding sites. We sought to identify new potential targets of resveratrol using an inverse docking approach that employs CANDOCK molecular docking algorithm26 and a database of predicted binding sites for the entire Protein Data Bank (PDB)27 using the ProBiS approach28. Inverse docking involves matching docking sites in many proteins to a molecule rather than the reverse, matching many molecules with a specific docking site. To validate our inverse docking approach, we first performed a re-dock procedure. Then novel protein targets were sought by docking resveratrol to the ~38,000 predicted binding sites. In addition, an alternative approach based on similarity of a binding site to those in the PDB with cocrystallized resveratrol using the ProBiS web server was used to identify new potential targets for resveratrol. The inverse docking approach as well as the binding site similarity approach both retrieved known resveratrol binding proteins as well as new potential targets, confirming the applicability of these approaches to the task of identifying targets for resveratrol.

Methods Inverse molecular docking Our prime intention was to find new protein targets to which resveratrol could potentially bind.26,28,29 Accordingly, we used the CANDOCK algorithm, a fragment docking algorithm developed in-house that treats receptors as flexible, to dock resveratrol into more that 38,000 protein structures from different organisms, of which around 13,500 were human proteins, obtained from the PDB. This algorithm uses a new knowledge-based method for scoring and a new fragmenting method for searching poses of ligands. Proteome-wide binding site preparation using ProBiS For inverse molecular docking we collected the small molecule binding site database29 from the PDB with all protein structures separated to their chains. The database was prepared with the ProBiS


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approach, available at http://insilab.org/probis-plugin, which calculates three-dimensional grid models of binding sites, focused on small ligand binding sites. These models define the size and the shape of predicted binding sites.29 The binding site database was updated recently to include newly released proteins.23 CANDOCK docking algorithm The CANDOCK docking algorithm uses hierarchical approach to reconstruct small molecule ligands from atomic grid using graph theory. The algorithm docks ligand fragments in a protein’s binding sites using an atomic grid and a pair-wise knowledge-based scoring to find the best-docked poses of fragments. These are later linked together using the fast maximum clique algorithm. In this way, we obtain a large number of ligand conformations in the target protein. A second step uses energy minimization procedures, that model the flexibility of the small molecule and the target protein within the docking procedure.26,28 As input to the algorithm we used the resveratrol structure, which was inversely docked, and a set of proteins from different organisms and the coordinates of their binding sites which were defined as multiple centroids. For each protein we considered poses with the lowest, i.e., best, predicted binding energy of resveratrol. As a result, we obtained a ranked list of protein-ligand complexes; from this list, we selected 25 proteins, i.e., 20 human and five from different organisms, with the highest docking scores. We searched for known connections of these proteins with diseases and for their interactions with resveratrol. We analyzed interactions between resveratrol and amino acids in the corresponding binding sites of the two complexes exhibiting the highest docking score using the PLIP (Protein-Ligand Interaction Profiler) web server.30 Binding site comparisons using the ProBiS web server


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In the PDB, there are known human proteins with which resveratrol is a ligand and the goal at this stage was to find protein structures that have binding sites structurally similar to those in these proteins. For this purpose, we used the ProBiS web server (http://probis.cmm.ki.si), developed at the National Institute of Chemistry in Ljubljana.31 The ProBiS web server is used to detect structurally similar binding sites and proteins in the PDB and it also allows similarity calculations between any two proteins in the PDB. It uses the ProBiS algorithm, that can align proteins with different folds, based on the spatial similarity of binding sites.22,32 We screened all the PDB protein structures containing resveratrol and used them as queries for the ProBiS web server. We searched for proteins with binding sites similar to those binding resveratrol. Structural similarity was determent with Z-score, which is the number of standard deviations from the mean data point. With Z-score we can determine how similar the selected protein is to the main protein compared with randomly selected proteins. The higher Z-score is, the more similar the proteins are. We considered similarities at distances of 7.0 Å around the bound resveratrol and considered human protein structures with the highest similarity to each of the 14 proteins and chose them according to the Z-score (≥ 2.00). Method validation To validate our method (Figure 2), we conducted a re-docking analysis using 24 crystal protein structures from the PDB that have a co-crystallized resveratrol bound to their binding site. We collected these crystal structures from the PDB and removed the co-crystallized resveratrol, but we left cofactors inside if they formed interactions with resveratrol. We then re-docked resveratrol to these proteins. To determine the validity of the method we calculated the root-mean-square deviation (RMSD) of atomic positions between co-crystallized and docked resveratrol in those crystal structures. We considered


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successfully docked poses to be those that exhibited an RMSD value of less than 2 Å towards the original crystal ligand.33 Figures of resveratrol in binding sites were prepared using UCSF Chimera.34

Figure 2. Workflow of the target prediction approach. For inverse molecular docking we used binding sites database prepared with the ProBiS approach from the Protein Data Bank (PDB) proteins.29 Inverse molecular docking and method validation were preformed using the CANDOCK algorithm26 and binding site comparison was preformed using the ProBiS web server31.

Results Novel protein targets of resveratrol in various organisms


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For the analysis of connections with diseases we selected five protein structures with the lowest binding energies from various organisms (Table 1), and 18 human proteins (Table 2). Table 1 shows the five proteins in which the predicted binding energy of resveratrol was most favorable. None of them are human proteins, but some are related to human diseases. Table 1. The potential resveratrol target proteins from various organisms. PDB ID with chain

Protein name

Organism

Predicted binding energy [arbitrary units*]

Protein function and reported connection with diseases

Known experimental correlation of protein with resveratrol

Known experimental correlation of organism with resveratrol

2y7iA

putative argininebinding periplasmic protein (STM4351)

Salmonella enterica Serovar Typhimurium

-53.5953

Classified as argininebinding protein, part of periplasmic binding protein family, important transport system components, required for bacterial growth and survival 25.

No

Yes 35,36

3epwA

IAG-nucleoside hydrolase

Trypanosoma vivax

-51.0604

Key enzyme of purine salvage pathway. No known connections with human diseases, known cause of diseases in domestic animals 28.

No

No

5dxiA

trehalose-6phosphate phosphatase

Candida albicans

-48.8638

Important in synthesis of Trehalose, which is important as stress protectant. Inactivation of protein results in accumulation of trehalose-6-phosphate, thermosensitivity and cell death 29.

No

Yes 37,38

4d5gA

cyclohexane1,2-dione hydrolase

Azoarcus sp. BH72

-47.3205

Catalysator of C-C bond cleavage of cyclohexane‐1,2‐dione to 6‐oxohexanoate and the asymmetric

No

No


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benzoin condensation between benzaldehyde and pyruvate. No connections with diseases found 32. 5jgfA

vacuolar Saccharomyces -47.3142 Serves as receptorNo Yes 39 aminopeptidase cerevisiae mediated cargo during 1 selective autophagy 33. * Predicted binding energies are knowledge-based docking scores with arbitrary units and represent relative binding energies of a ligand to a protein.

Putative arginine-binding periplasmic protein (STM4351) has the lowest potential binding energy for resveratrol in our set of target proteins. This protein is found in Salmonella enterica serovar Typhimurium, which is a common cause of food poisoning. Resveratrol is already known to decrease the proliferation and viability of S. Typhimurium and could potentially be used as a drug. It can also lower the rate of apoptosis of infected human cells.35,36 There are no known connections of STM4351 with resveratrol, but we identified it as potential target protein, which is subject to inhibition by resveratrol (Table 1). Inhibition of this protein could lead to reduction of bacterial growth or possibly, apoptosis of S. Typhimurium bacteria. Protein IAG-nucleoside hydrolase is found in Trypanosoma vivax. Different species from Trypanosomatidae family cause a variety of diseases in human and animals. There are no known connections between Trypanosoma vivax and resveratrol, but resveratrol has shown strong anti-parasitic effects in connection with Trypanosoma cruzi. It is known to be an inhibitor of multiple proteins from T. cruzi. Because of these connections, it is reasonable to assume that resveratrol could inhibit other proteins, found in different species from Trypanosomatidae family, including the IAG-nucleoside hydrolase from T. vivax. Inhibition of this protein could be reflected in reduced synthesis of purine nucleosides, which are essential for parasitic survival.40,41


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Trehalose-6-phosphate phosphatase protein is one of the main targets for inhibition in yeast Candida albicans, an opportunistic pathogenic yeast that is a cause of systemic microbial infections. There are few studies of C. albicans which discuss the activity of resveratrol and the potential for its inhibition, and the results are inconclusive. We propose trehalose-6-phosphate phosphatase to be a potential target for resveratrol. This protein participates in the synthesis of trehalose, which is important in microbial growth, because it protects proteins and membranes under stress conditions. Inhibition of trehalose-6phosphate phosphatase would result in accumulation of trehalose-6-phosphate, which is very toxic to cells and whose presence can lead to apoptosis. All those proteins are absent in mammals, so trehalose could be a promising target for treatment of C. albicans infections.37,38,42 Cyclohexane-1,2-dione hydrolase belongs to the group of thiamine diphosphate dependent enzymes. There are no known connections to any disease, and few indications of the possible effects of inhibition of such enzymes. Azoarcus sp. BH72 is bacterium, found in Kallar grass and rice. There are no indications for pathogenicity of Azoarcus sp. BH72, but there is significant increase of plant biomass, if rice is inoculated with these bacteria.43–45 The exact function of the protein is unknown and so the effects of its inhibition by resveratrol are unknown. Protein aminopeptidase 1 is a vacuolar hydrolase found in yeast Saccharomyces cerevisiae. The yeast is very common in the baking and brewing industries, and it can also be used as a probiotic. It can be however, an uncommon cause of infections in humans. S. cerevisiae was previously connected with resveratrol, because it contains a few important substrates that are crucial in the production of resveratrol in red wine. Aminopeptidase 1 is a major selective cargo protein in yeast and is important during selective autophagy. It has no known connections with resveratrol, but our research proposed its potential inhibition with resveratrol. As the protein is important in disposal of unnecessary or


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dysfunctional components in cells, its inhibition with resveratrol could stop autophagy, which could result in accumulation of unusable or toxic components.39,46,47 We then analyzed the 20 human proteins with the lowest docking scores as protein targets for resveratrol (Table 2). Many of these proteins have multiple PDB entries corresponding to complexes with different ligands, and therefore we excluded proteins with non-unique sequences. Table 2. The potential human target proteins of resveratrol. PDB ID with chain

Protein name

Predicted binding energy [arbitrary units*]

Protein function and reported connection with diseases

Known experimental correlation with resveratrol

References

3h5cB

vitamin K-dependent protein Z

-47.2125

Plasma glycoprotein, that plays an important role in blood coagulation. Cofactor for inhibition of factor X. Protein Z/ZPI system connected with thrombosis, coronary syndromes, stroke, nephrotic syndrome.

No

48,49

5ab2A

endoplasmic reticulum aminopeptidase 2 (ERAP2)

-46.2235

Regulation of the antigenic peptide repertoire, influencing cytotoxic immune responses, shaping epitope immunodominance. Potential link with resistance to HIV infection and association with predisposition to cancer and other MHC-connected diseases.

No

50

5e1dA

N-terminal methyltransferase 1 (NTMT1)

-45.1385

Catalyst of the N-terminal methylation of various proteins. Knockdown of NTMT1 leads to hypersensitivity or intolerance of breast cancer cells to etoposide and γ-irradiation treatments, also higher mortality rate and premature aging of mice.

No

51

3zmvA

lysine-specific histone demethylase 1A

-44.4614

Catalyst of the removal of mono- or dimethyl groups from proteins. Involvement in cancer, neurodegeneration and viral infection.

Yes 52

53

3fedA

glutamate carboxypeptidase III

-44.2817

Metalloenzyme, homolog glutamate carboxypeptidase

No

54

to II,


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which is a transmembrane metallopeptidase, found in brain, small intestine, and prostate. Biological significance is not yet known. 1i3oE

baculoviral IAP RepeatContaining Protein 4

-43.9549

Antiapoptotic protein, potent caspase inhibitor, potential approach for treatment of human glaucoma. Connection with glaucoma, Wilson disease.

No

55,56

4cqlE

estradiol 17-betadehydrogenase 8

-42.9049

Short-chain alcohol dehydrogenase, enzyme, catalysator of reversible interconversion of 17beta-estradiol and estrone, reduction of 16alphahydroxyestrone to estriol (estrogen in human pregnancy) and the oxidation-reduction of some androgens and progesterone. Dysfunctions result in disorders in reproduction and neuronal diseases, also found in cancers.

No

57,58

2hyvA

annexin A2

-42.7037

Important in various processes, like membrane trafficking, cell signaling apoptosis and inflammation. Present in most cancers’ cells.

No

10,59

1fj2A

acyl protein thioesterase I

-42.5917

Catalyst of depalmitoylation of Gα.

No

60

1q92A

5(3)deoxyribonucleotidase

-42.5489

Enzyme, that dephosphorylates nucleotides to their corresponding nucleosides. Important role in controlling the activation of nucleotide-based drugs against viral infections or cancer.

No

61

2jgbA

eukaryotic translation initiation factor 4e type 2

-42.5256

Plays an important role in capdependent translation initiation. Anchors the 5’ end of mRNA by binding to the cap. Part of eIF4F complex, responsible for recruiting the 40 S ribosomal subunit to the 5’ end of mRNA.

No

62

5gnrA

mitofusin-1

-42.4899

Controls mitochondrial morphology with regulating fusion of mitochondria. Important for neuron glucosesensing and insulin release control, diabetes.

No

63,64

4edyA

hematopoietic prostaglandin D

-42.4697

Found in mast and Th2 cells. Forms prostaglandin D-2, which is

No

65


13


synthase

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important mediator of allergic and inflammatory processes. When inhibited, potential target for development of anti-allergic and anti-inflammatory drugs.

4y30A

protein Arginine Nmethyltransferase 6 (PRMT6)

-42.4569

Connected with a variety of cellular processes, like regulation of cell cycle, DNA repair, viral transactivation. Regulates gene transcription. Able to methylate histones. Connected with cancer, spinal and bulbar muscular atrophy.

No

66–68

4yhjA

G protein-coupled receptor kinase 4 (GRK4)

-42.3899

Phosphorylation of G-proteincoupled receptor family. GRK4 found in testis, cerebellum and kidney. Dysregulation of GRK4 can be implicated in cardiac disease, Parkinson disease and some other diseases.

No

69

2x2eA

dynamin-1

-42.0596

GTPase, catalyst of membrane fission during clathrin-mediated endocytosis. Expressed in brain and acts as microtubuleand phospholipid-binding protein. Connected with neurodegenerative diseases.

Yes 70

71,72

2hkoA

lysine-specific histone demethylase 1

-41.8640

Histone demethylase, demethylates monomethylated and demethylated histone H3K4. Up regulated in cancer, inhibition may have therapeutic values.

Yes52

73

1ek6A

UDP-galactose 4epimerase

-41.8544

Catalyst of the second step in the Leloir pathway of galactose metabolism. Impairment results in complex disorder galactosemia.

No

74

* Predicted binding energies are knowledge-based docking scores with arbitrary units and represent relative binding energies of a ligand to a protein.

Novel protein targets of resveratrol in human proteome


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We analyzed the most promising protein targets of resveratrol discovered by inverse molecular docking to the human structural proteome and the results are listed in Table 2. Protein Z, a vitamin K-dependent plasma glycoprotein, is important in reducing coagulation. Deficiency of protein Z could result in a prothrombosis. There are no known connections with resveratrol, but we could postulate, that with inhibition of protein Z, regulation of blood coagulation could be controlled. There are known connections of resveratrol with anticoagulant proteins C and S, where resveratrol down-regulates their expressions.48,49,75 Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) are proteins, that optimize peptides, which bind to MHC class I molecules, where they assist with the trimming of N-terminally extended precursors of mature epitopes. MHC molecules are a set of proteins essential for the immune system functioning, so the inhibition of ERAP proteins could affect the immune system. These proteins are connected with various diseases, such as ankylosing spondylitis, birdshot chorioretinopathy and psoriasis, as well as Crohn’s disease, hypertension and preeclampsia.50,76–78 The protein NTMT1 methylates α-N-terminal amines. It is upregulated in a variety of cancers, so its inhibition could result in cell defects. Inhibition of this protein is thought to have potential as an anticancer therapy.51,79 Lysine-specific histone demethylase 1A (LSD1) is a flavoenzyme that selectively demethylates the lysine in histones. It plays important rolls in cell growth, differentiation, and is implicated in cancer, neurodegeneration and viral infections. Inhibition of LSD1 has already been examined as an approach for cancer treatment, and resveratrol is already known to be a potential inhibitor of LSD1.52,53,80 Protein glutamate carboxypeptidase III (GCPIII) is a metalloenzyme from MEROPS M28 peptidase family. There is no clear indication of its role in human cells and thus nothing is known about the possible effects of its inhibition.54,81


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Baculoviral IAP Repeat-Containing Protein 4 (BIRC4) is an inhibitor of proteins that are involved in apoptosis. There are a few known connections of inhibition of BIRC proteins with cancer treatment, glaucoma, or Wilson disease. Resveratrol is already known to be an inhibitor of IAPs, but there is no known connection with BIRC4, so resveratrol could be involved in a new approach to regulation of apoptosis.55,56,82 Estradiol 17-beta-dehydrogenase 8 is one of several enzymes that regulate the biological activity of steroid hormones. Dysfunction of this protein could lead to reproductive disorders and neuronal diseases. This enzyme is also connected to pathogenesis of various cancers. As the protein is both an estrogen and an androgen inactivator, resveratrol could possibly be used as an inhibitor to control the levels of steroid hormones.57,58 Detailed analysis of interactions of resveratrol and selected target proteins For a detailed analysis of intermolecular interactions, we chose the highest-ranking protein in both sets. These are the putative arginine-binding periplasmic protein (STM4351) from S. enterica serovar Typhimurium bacterium, and human vitamin K-dependent protein Z (PZ). With its three hydroxyl groups, π-π interactions and π-cation interactions from its two aromatic rings, resveratrol has a significant potential to form hydrogen bonds and aromatic interactions with proteins. Because of the presence of hydrophobic amino acids in the binding sites, hydrophobic interactions with resveratrol are also possible. In the binding site of protein STM4351 resveratrol is bound with five hydrogen bonds, while hydrophobic interactions with Tyr159, Tyr33, Phe71, Thr139 and Asp91 are recognized. Moreover, π-stacking with Tyr33 and π-cation interaction with His140, as is presented on Figure 3, are also observed. Strong hydrogen bonds and a semi-strong π-interactions and hydrophobic interactions most likely lead to strong binding of resveratrol to the binding site of protein STM4351, which is also consistent with a high docking score from CANDOCK with the value of -53.59.


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Resveratrol in the binding site of vitamin K-dependent protein Z showed only two hydrogen bonds and formed hydrophobic interactions with Leu331, Gln334, Ala340 and Val343 (Figure 4), which is reflected in somewhat higher docking score of -47.21.

Figure 3. Analysis of interactions between the binding site in the protein putative arginine-binding periplasmic protein (STM4351; light blue) and resveratrol (orange). Hydrogen bonds are labeled with blue lines, π-π stacking is labeled with a green line, the π-cation interaction is labeled orange and hydrophobic interactions are labeled grey.


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Figure 4. Analysis of interactions between the binding site of vitamin K-dependent protein Z (light blue) and resveratrol (orange). Hydrogen bonds are labeled with blue lines and hydrophobic interactions are labeled grey. Binding site similarity between predicted target proteins and known resveratrol binders We also performed analysis of binding site similarity with the ProBiS web server to determine if there are known binders of resveratrol that have binding sites similar to those in the newly discovered target proteins. Currently, there are 14 human protein structures with bound resveratrol in the PDB. We compared these structures, using the ProBiS web server against the PDB, which resulted in a list of proteins containing similar binding sites to those in the 14 known resveratrol binders (Table 3).


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Table 3. Protein structures with co-crystallized resveratrol and the identified proteins with similar binding sites. PDB ID with chain (crystal structure)

Protein name

1dvsA

transthyretin

1sg0AB

2l98A

2ydxABCDE

3cklAB

3ftsA

NRH dehydrogenase [quinone] 2

troponin C (slow skeletal and cardic muscles)

methionine adenosyltransferase 2 subunit beta

sulfotransferase family cytosolic 1B member 1

leukotriene A-4 hydrolase

Similar proteins PDB ID with chain

Protein name

Zscore

1f86A

transthyretin THR119MET variant

3.10

4fglA

ribosyldihydronicotinamide dehydrogenase [quinone]

3.67

1d4aA

quinone reductase

2.19

2k7bA

calcium-binding protein 1

2.38

3lcpC

multiple coagulation factor deficiency protein 2

2.24

1j55A

S-100P Protein

2.18

1ggzA

calmodulin-related protein NB-1

2.07

1ek6A

UDP-galactose 4-epimerase

2.04

2a3rA

monoamine-sulfating phenol sulfotransferase

3.11

2reoA

putative sulfotransferase 1C3

3.34

1g3mA

estrogen sulfotransferase

3.04

1ls6A

aryl sulfotransferase

3.23

2gwhA

sulfotransferase 1C2

3.01

1q20A

sulfotransferase family, cytosolic, 2B, member 1 isoform b

2.69

1q1qA

sulfotransferase family, cytosolic, 2B, member 1 isoform a

2.60

1j99A

alcohol sulfotransferase

2.16

4pj6A

leucyl-cystinyl aminopeptidase

2.44

4fytA

aminopeptidase N

2.42


19


4hdaB

4jazA

4pp6AB

NAD-dependent protein deacylase sirtuin-5, mitochondrial

peroxisome proliferator-activated receptor gamma

estrogen receptor

Page 20 of 37

2yd0A

endoplasmic reticulum aminopeptidase 1

2.40

4jbsA

endoplasmic reticulum aminopeptidase 2

2.11

3riyA

NAD-dependent deacetylase sirtuin5

2.54

5btrA

NAD-dependent protein deacetylase sirtuin-1

2.35

4bn4A

NAD-dependent protein deacetylase sirtuin-3, mitochondrial

2.31

4rmhA


2.08

3vi8A

peroxisome proliferator-activated receptor alpha

2.67

3tkmA

peroxisome proliferator-activated receptor delta

2.17

3ollA

estrogen receptor beta

3.40

2e2rA

estrogen-related receptor gamma

3.28

3k6pA

steroid hormone receptor ERR1

2.84

4pf3A

mineralocorticoid receptor

2.75

1sr7A

progesterone receptor

2.61

4ohaA

androgen receptor

2.55

3gn8A

glucocorticoid receptor 2

2.56

4q93A

tyrosine-tRNA ligase, cytoplasmic

1n3lA

tyrosil-tRNA synthetase

3.67

4qohAB


1d4aA

quinone reductase

2.29

4qojAB


1d4aA

quinone reductase

2.17

4rmhA


3.14

4bn4A

NAD-dependent protein deacetylase sirtuin-3, mitochondrial

2.74

5btrABC



20

Page 21 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


5cr1B

transthyretin

3pkiA


2.52

3riyA


2.50

1f86A

transthyretin THR119MET variant

3.61

We compared these results with those obtained from the inverse docking to determine if there was any overlap. We found two overlapped proteins, UDP-galactose 4-epimerase and endoplasmic reticulum aminopeptidase 2. Using inverse docking, we found a potential target protein UDP-galactose 4epimerase (PDB ID: 1ek6A; Table 2). Judging by the results from analysis of binding site similarity with the ProBiS web server, this protein has a structurally similar binding site to the binding site in the known resveratrol binder methionine adenosyltransferase 2 subunit beta (PDB ID: 2ydx; Table 3). Another protein discovered using inverse docking is endoplasmic reticulum aminopeptidase 2 (ERAP2; PDB ID: 4jbsA; Table 2), which is structurally similar to the known resveratrol binder leukotriene A-4 hydrolase (PDB ID: 3fts; Table 3). Finding the same proteins using two different approaches supports our predictions. Validation of the CANDOCK algorithm To validate this algorithm, we used the re-docking procedure. We obtained 24 protein crystal structures with co-crystallized resveratrol from the PDB. We left cofactors in binding sites if they formed interactions with resveratrol. For each protein structure, we considered the three highest scoring poses of resveratrol obtained with CANDOCK and for each pose we calculated the RMSD between the docked resveratrol and the co-crystallized resveratrol from the PDB. We considered the docking to be successful if any of the docked resveratrol poses was within 2 Å of the co-crystallized pose. We also used the


21


Page 22 of 37

binding Mother of All Databases83 (binding MOAD) to search for the binding affinity data for these proteins. Table 4. Results of the method validation. PDB ID with chain (crystal structure)

Predicted binding energy [arbitrary units]

RMSD [Å]

Good fit*

Binding Affinity (Sequence Identity [%]***)

1cgzA

-35.388

4.2881**

No

/

1dvsA

-12.1803

1.2463

Yes

/ IC50: 450 - 6900 nM (99)

1sg0B

-27.5871

1.2958

Yes

Ki: 88 nM (99) Kd = 35 – 88 nM (99)

1u0wA

-30.9819

0.7333

Yes

/

1z1fA

-29.3325

4.0150**

No

/

2jizN

-27.1564

1.2136

Yes

/

2l98A

-20.0371

2.0119

No

Kd: 243000 nM (100)

2ydxA

-28.5058

1.2065

Yes

/

3cklA

-24.5124

1.2495

Yes

/

3ftsA

-28.932

1.1966

Yes

IC50: 212000 - 366000 nM (100)

3mnqA

-29.0355

1.7705

Yes

/

4dpnA

-23.7177

2.6310

No

/

4hdaB

-13.8105

2.2948

No

/

4jazA

-28.0502

1.0746

Yes

/

4pp6A

-36.0636

1.0562

Yes

/

4q93A

-23.8297

1.2036

Yes

/

4qerA

-28.6547

1.1778

Yes

/ IC50: 450 - 6900 nM (99)

4qohA

-20.9114

1.8130

Yes

Ki: 88 nM (99) Kd: 54 nM (99)

4qojA

-27.5546

1.8230

Yes

IC50: 450 - 6900 nM (99)


22

Page 23 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Ki: 88 nM (99) Kd: 54 nM (99) 5btrA

-35.1968

1.2615

Yes

EC50: 23600 - 46200 nM (98)

5cr1B

-15.5607

1.6278

Yes

IC50: 2188 - 10500 nM (99)

5j54A

-21.6251

1.4019

Yes

/

5nzlA

-25.004

2.9258

No

/

5u90C

-29.2297

1.2124

Yes

/

* Good fit was determined according to the RMSD threshold of 2 Å between any of the first three best scored docked poses and the crystal structure of resveratrol.33 ** Reversed conformation. *** Values in parentheses indicate percent of sequence identity to a protein in which binding affinity was measured.

Upon comparison of the experimental pose of resveratrol in the sulfotransferase family cytosolic 1B member 1 protein (PDB ID: 3ckl) with the pose obtained by re-docking using CANDOCK, we found that the highest scoring re-docked resveratrol (docking score of -24.5) is in a very similar pose (RMSD value of 1.25 Å) to that of the co-crystallized resveratrol (Figure 5); this, according to our RMSD threshold of 2 Å, indicates a good fit. The second protein used for re-docking was the estrogen receptor (PDB ID: 4pp6). Here, the comparison of the co-crystallized pose of resveratrol to the highest scoring (docking score of -36.1) pose obtained by re-docking revealed a significant overlap (Figure 6) with the RMSD of 1.06Å. However, the protein structure for the estrogen receptor contains two alternative cocrystallized conformations of resveratrol, of which one is reversed in relation to the other, as shown in Figure 6. There is one more such resveratrol-bound protein structure in the PDB (PDB ID: 2jiz), which led us to believe that both such conformations of resveratrol are possible. In our validation, we encountered two proteins (PDB IDs: 1cgz, 1z1f), in which the docking produced a reversed conformation of resveratrol relative to the co-crystallized pose. Such cases could be regarded as good fits as well despite their apparently high (~4 Å), RMSD values.


23


Page 24 of 37

Figure 5. Comparison of the re-docked and the co-crystallized resveratrol poses in the sulfotransferase family cytosolic 1B member 1 protein (PDB ID: 3ckl). Docked resveratrol (green) overlaps well with the co-crystallized resveratrol (orange) with the RMSD value of 1.25 Å. Protein is presented as blue cartoon model.


24

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Figure 6. Comparison of the re-docked and the co-crystallized resveratrol poses in the estrogen receptor (PDB ID: 4pp6). Docked resveratrol (yellow) is compared to the two alternatively oriented cocrystallized poses of resveratrol (blue and light blue) in the crystal structure. The RMSD value to the most similar co-crystallized pose is 1.06 Å. Protein is presented as light purple cartoon model. The difference in scores in Tables 1 and 2 for new resveratrol targets in comparison to scores reported in Table 4 for known resveratrol binding proteins may be due to the new protein targets being better resveratrol binders than the already known targets. Other polyphenols have been shown to bind to multiple proteins,84 and therefore it is very likely that many of the resveratrol targets are still unknown.

Conclusion We report new potential targets of the polyphenol resveratrol from a set of ~38.000 protein structures, found in different organisms, using the ProBiS binding site comparison together with the CANDOCK docking algorithm, in a new inverse docking approach. We found several proteins from infectious organisms to be potential targets of resveratrol. We also found potential resveratrol targets among the human protein structures that have been implicated in various diseases and cancers. New potential targets for resveratrol include endoplasmic reticulum aminopeptidase 2 that regulates the antigenic peptide repertoire, influence immune responses, and has a significant effect on epitope immunodominance. This aminopeptidase protein is connected with a variety of diseases, such as ankylosing spondylitis, birdshot chorioretinopathy and Crohn’s disease, so we assume that inhibition of the protein with resveratrol could be used as new potential therapy.50,78 This protein is structurally similar to an existing crystal structure with co-crystallized resveratrol. The development of fast and accurate approaches for the inverse molecular docking is very important. Improvement of the current approaches could lead to the repurposing of existing drugs, to the discovery of yet unknown risks and


25


Page 26 of 37

potential side effects of current drugs, to the design of potential drug candidates by minimizing crosseffects, and to accelerated discovery of new natural products. Our approach is universal, and its results can serve as a starting point for further research and for the design of biochemical experiments.

Acknowledgments This work is supported by the Slovenian Research Agency project grants, L7-8269: New approaches for better biopharmaceuticals, J1-9186: New computational tools at the PDB scale for drug discovery, and J1-6736: Chemical Carcinogenesis - A Computational Approach and by the Ministry of Education, Science and Sport of Republic of Slovenia project grants: AB FREE and F4F. We also gratefully acknowledge the support of NVIDIA Corporation with the donation of two Tesla K40 GPUs and two Tesla K80 GPUs used for this research.

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Discovery of Novel Potential Human Targets of Resveratrol by Inverse

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