Molecular Modeling of 5HT 2A Receptor - Arylpiperazine Ligands...

Molecular Modeling of 5HT2A Receptor – ArylpiperazineLigands Interactions

Milan Sencanski1,*, Vladimir Sukalovic2,*, KavehShakib3, Vukic Soskic4, Ljiljana Dosen-Micovic5

and Sladjana Kostic-Rajacic2

1Innovation Center of the Faculty of Chemistry, Universityof Belgrade, Studentski trg 12-16, Beograd 11000, Serbia2ICTM – Centre for chemistry, University of Belgrade,Njegoseva 12, Belgrade 11000, Serbia3Barnet & Chase Farm Hospital, The Ridgeway, Enfield,Middlesex, EN2 8JL, UK4ORGENTEC Diagnostika GmbH, Carl-Zeiss-Street 49-51,Mainz, Germany5Faculty of Chemistry, University of Belgrade, Studentskitrg 12-16, Beograd 11000, Serbia*Corresponding authors: Vladimir Sukalovic,[email protected]; Milan Sencanski,[email protected]

In this paper, we report the molecular modeling of the5HT2A receptor and the molecular docking of arylpiper-azine-like ligands. The focus of the research was onexplaining the effects the ligand structure has on thebinding properties of the 5HT2A receptor and on thekey interactions between the ligands and the receptor-binding site. To see what the receptor–ligand inter-actions were, various substituents were introduced inone part of the ligand, keeping the rest unchanged. Inthis way, using a docking analysis on the proposed5HT2A receptor model, we identified key receptor–ligand interactions and determined their properties.Those properties were correlated with experimentallydetermined binding affinities in order to determine thestructure to activity relationship of the examined com-pounds.

Key words: arylpiperazine, docking simulations, molecularmodeling, serotonine

Abbreviations: 5HT2A, serotonine receptor type 2; ETF,edge-to-face; ESP, electronic surface potential.

Received 5 September 2013, revised 30 October 2013 andaccepted for publication 4 November 2013

G-protein-coupled receptors (GPCRs) are a large familyof integral membrane proteins that have been the focus ofpharmaceutical research in recent years. Almost 30% ofapproved drugs are targeting GPCRs (1). There are about360 pharmaceutically relevant GPCRs in the human

genome that have been identified, but so far, crystal struc-tures have been determined for only a few (2). Because ofthat, in silico homology modeling is the method of choice,for creating the receptor model used in the discovery of newligands.

5-Hydroxytryptamine (5HT) is one of the major neurotrans-mitters in the central nervous system (CNS) and plays acrucial role in the regulation of mood, appetite, and sleep.Modulation of 5-hydroxytryptamine homeostasis in CNS isconsidered to be a mode of action for several classes ofantidepressants (3,4).

There are seven different classes of receptors for 5-hydro-hytryptamine, all but one (5HT3) belong to the GPCR fam-ily. In this study, we focused on the 5HT2A receptorsubtype that is a prominent target for many antipsychoticdrugs. 5HT2A receptor is expressed in various CNSregions where it has, upon the anatomical localization,excitatory or inhibitory functions (5).

Our current research program is orientated in the directionof designing new pharmacologically active compounds thathave arylpiperazine as a common structural motive.Arylpiperazine belongs to the so-called privileged structures(6) and is present in the ligands that are targeting 5HT2Areceptor in CNS. The three dimensional (3D) structure of the5HT2A receptor has not been published so far; therefore toovercome that hurdle, we generated a in silico, homologymodel of the receptor using b2 adrenergic receptor (7) as atemplate. Further optimization and refinement were carriedout using an explicit membrane molecular dynamics simula-tion. Further tests included the receptor interaction with anumber of known ligands (Table 1) and their correlation withexperimentally obtained receptor–ligand-binding data. Theusefulness of the new 5HT2A model was demonstratedthrough a docking analysis of the active arylpiperazines thatwere published by other authors (Table 2) and the selectedactive and inactive compounds from published EuropeanBioinformatics Institute ChEMBL database.a

Methods and Materials

Modeling of 5HT2A receptor5HT2A receptor was modeled using SWISS-MODEL (8,9)modeling server. The full sequence of human 5HT2A

462 ª 2013 John Wiley & Sons A/S. doi: 10.1111/cbdd.12261

Chem Biol Drug Des 2014; 83: 462–471

Research Article

Table

1:Investigatedligandstructureswith

corresp

ondinginteractio

nswith

the5HT2Abindsite

Chem Biol Drug Des 2014; 83: 462–471 463

Molecular Modeling of 5HT2A Receptor

Table

1:Contin

ued

464 Chem Biol Drug Des 2014; 83: 462–471

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receptor was downloaded from NCBI database,b and thehigh-resolution crystal structure of inactive conformation ofb2 adrenergic receptor (PDBID 3D4S) was used as a tem-plate. Sequences were aligned, and a model was built.The best 5HT2A model was selected by means of theirRMSD and by the evaluation of the back-bone conforma-tion to verify protein model quality.

To relax the obtained model structure, we performed anexplicit membrane molecular dynamics simulation. 5HT2Awas inserted into a POPC lipid bilayer with dimensions70 9 70 �A, using the VMD 1.9.1 program (10). The systemwas combined using tcl script. The additional 5-�A-thickwater layers were added on both sides of the z-axis of thesystem, followed by neutralization (by adding 0.15M NaCl),to simulate physiological conditions. The final numberof atoms in the system was 38 990, and the final dimen-sions of the simulation cell were 75 9 73 9 89�A.A CHARMM22 force field (11) was used for protein andlipids. The obtained system was set to cascade 10 000steps minimization, 250 ps equilibration, and 10 nsproduction on 310K under PBC conditions in NVT ensem-ble running in NAMD 2.7b program (12). The integration stepwas 1 fs. The cut-off was set to 12�A. After the plotting ofthe potential energy graph and its derivative with respectto simulation time, we concluded that the system reachedenergetic stability (Figure S1). All calculations were carriedout on PARADOX computer cluster (13) and a personalPC system. In order to validate the proposed model qual-ity, a Ramachandran diagram was generated using PRO-

CHECK online (14,15) and the receptor structure wasobtained after molecular dynamics optimization.

Ligand construction and molecular dockingLigand structures were drawn in ACD CHEMSKETCH 11.0,c

and their 3D structures were generated using Avogadro1.0.0.d Assuming physiological conditions, the basic ali-phatic nitrogen atom of the piperazine was protonated.The geometry was optimized using the MMFF94 force field(16) followed by the PM6e semi-empirical method imple-mented in MOPAC 2009 (17).e

All ligands and receptors were prepared for docking inADT Tools 1.5.6 (18,19). Molecular docking was per-formed in AUTODOCK Vina 1.1.1 (20). The grid box dimen-sions were set to 22 9 22 9 22 �A3, and its center wasset to span all crucial amino acid residues identifiedaccording to previous studies (21–25). Exhaustiveness wasset to 100. Number of output conformations was set to250. The searching seed was random. The obtained dock-ing structures were further filtered and based on the fol-lowing criteria: (i) lowest binding energy and (ii) shortestsalt bridge to the receptor amino acid residue Asp 155.

Preferred protein-ligand complexes, obtained by dockinganalysis, were chosen for further optimization. Qm/mmoptimization was carried out, using QSite application in

Table 2: Selected literature 5HT2A ligands



Schrodinger 2011 for Windows (26,27). Ligand was trea-ted ab initio on DFT/B3LYP level of theory using 6-31G*basis set, and protein with OPLS 2005 force field. Proteinbackbone atoms were held frozen. Optimized complexeswere isolated, and protein–ligand interactions were deter-mined.

Electronic Surface Potential and AlogP calculationLigands, designed as previously described, were furtheroptimized in Gaussian 03W software (28), using the DFT/B3LYP method, with 6-31G* basis set. Geometry opti-mized in this way was used for the calculation of electronicsurface potential (ESP).

AlogP calculation was carried out using Canvas module inSchrodinger 2011 for Windows (26).

Model validationModel validation was carried out with a binary set ofligands from the ChEMBL 5HT2A database.a We selecteda total of 40 ligands, 20 active, and 20 inactive. All ligandswere prepared as described and docked into the pro-posed 5HT2A model using Glide application in Schrodinger2011 for Windows.

Results visualizationStructures were visualized using DS Visualiser v3.1, (29)and the obtained images were rendered using PovRayRaytracer v3.6.f Electronic surface potential surfaces werevisualized using gOpenMol program (30,31).

Results and Discussion

The 5HT2A receptor model was built using available co-ordinates of human b2 adrenergic receptor as a template.5HT2A and b2 adrenergic receptor have 23.2% similarity(115 identical and 149 similar residues). Extensive model-ing of loop areas was not attempted, as they do not formthe receptor-binding site and directly interact with theinvestigated ligands.

The proposed model was subjected to explicit membranesimulations, in order to relax the obtained protein confor-mation and to prove its stability. The system setup wasassembled as described before, and simulation was set torun until completed (Figure S1). After the moleculardynamics optimization of the receptor, in order to validatemodel quality, a Ramachandran diagram was generated.The plot statistics were the following: residues in mostfavored regions 276 (92.6%), residues in additional allowedregions 19 (6.4%), residues in generously allowed regions1 (0.3%), and residues in disallowed regions 2 (0.7%). Themodel has over 90% residues in most favored regions, giv-ing us a good quality model (Figure S2; c).

For the sake of clarity, the molecular structure of the ligandwas divided into three distinct substructure motives: vari-able head part, linker, and tail piperazine part (Table 1).Compounds were sorted out in distinct subsets accordingto the similarities in structure (Table 1). Docking was car-ried out, using a rigid receptor and flexible ligand setup.Results of docking analysis showed that all investigatedligands bind to 5HT2A receptor in a similar manner(Figure 1). Key receptor–ligand interactions are as follows:short salt bridge between Asp 155 and the protonatednitrogen ligand atom and the hydrogen bond between theligand head part and Asn 343. These two interactionsestablish a correct ligand orientation: tail part binds intothe nearby binding pocket formed by Leu 123, Ser 159,Trp 336, Phe 339, Val 366, and Tyr 370, while the headpart fits into the second binding pocket formed by Trp151, Ile 152, Leu 229, Ala 230, Phe 234, and Val 235.Those findings are supported at least in part, by experi-mental results, as Asp 155, Ser 159, Trp 336, Phe 339,and Tyr 370 (21–25) were previously determined by a pointmutation study as key amino acid residues for high 5HT2Aaffinity.

Ligand set 1 (compounds 1–7) (32–34): in case of ligands1 and 6, interactions between the tail part and the bindingpocket are aromatic, most probably edge-to-face (ETF)and/or hydrophobic in nature (Figure 2). Receptor aminoacid residues Trp 336, Phe 339, and Tyr 370 can formETF interactions, while Leu 123 and Val 366 will contributeto hydrophobic interactions. Ligands 2–4 and 7, havingdifferent substituents in the tail part, can form a hydrogenbond (or electrostatic interactions) with either Ser 159 orTyr 370 (Figure S3). Ligand affinity is influenced by numberand strength of corresponding interactions. Ligands 1 and6 can form multiple ETF interactions (ligand acts as facefor Trp 336 and Tyr 370, and edge for Phe 339). Ligand 6

has higher affinity compared with 1 as naphthyl group ofligand 6 has a larger and more accessible face area thanthe corresponding phenyl group present in ligand 1.Ligands 2 and 7 can form hydrogen bonds. In the case ofligand 2, that hydrogen bond is formed with Ser 159, whilesome of the ETF interactions are maintained. Ligand 7

cannot form the same ETF interactions, because the intro-duction of the nitro group alters ESP in a way that ligandlose its partially negative charge in the face area. On theother hand, increased affinity of ligand 7 can be explainedby the formation of two hydrogen bonds with Ser 159 andTyr 370, together with edge interaction with Phe 339.

Ligands 3 and 4 have a similar ESP to ligand 7 (center ofaromatic ring is less negative, because of the introductionof a halogen atom), but still can act as an edge to Phe339. Ligand 4 can form a hydrogen bond with Ser 159 orTyr 370, while ligand 3 benefits only from electrostaticinteractions.

Ligand 5 has the lowest affinity in the whole series. It hasan unfavorable ESP distribution, and distances between


Sencanski et al.

the arylpiperazine ligand tail part and Ser 159/Tyr 370 aretoo great for an effective hydrogen bond.

Ligand set 2 (compounds 8–17) (35): Ligands 8–17 have thesame tail and linker part, with a different substituent in thehead part. Docking analysis shows that they share commoninteractions with 5HT2A receptor: salt bridge between ligandand Asp 155, hydrogen bond with Asn 343, and aromaticinteractions with the binding pocket formed by Leu 123, Ser159, Trp 336, Phe 339, Val 366, and Tyr 370 and hydrogenbond with Ser 159 (Figure 3). The head part of the ligandcan form additional interactions with the receptor, based onits shape, size, and functional groups with Trp 151, Ile 152,Leu 229, Ala 230, Phe 234, and Val 235.

Ligands 9, 10, and 12 can form a hydrogen bond withAsn 343. Their affinity is higher than ligand 8, which can

benefit only from a hydrophobic interaction with Ile 152,Leu 229, Ala 230, and Val 235, with the possibility of ETFinteractions with Trp 151 and Phe 234.

All para substituted ligands (10, 13, 16) have a lower affin-ity than ligand 8, because of the steric hindrance betweenthe ligand head and Phe 234 of the receptor. This alsoholds true, for a number of bulky meta substituted ligands(13 and 16) as well as for ligands 15, 16, and 17 that aretoo bulky to form a hydrogen bond with Asn 343.

Ligand set 3 (compounds 18–27) (32): Introduction of hal-ogen atom in the benzimidazole head part increases theoverall affinity of the ligand (Table 1.). When compared tounsubstituted substances, the observed affinity increase istwo (in case of R:Cl) and four times (in case R:Br). Thepositive affinity trend is strong in all the investigated ligands

Figure 3: Docking analysis of the5HT2A receptor receptor and ligand12 (left) and ligand 21 (right). Onlykey amino acid residues are shownfor clarity.

Figure 2: Docking analysis of the5HT2A receptor receptor and ligand1 (left) and ligand 7 (right). Only keyamino acid residues are shown.

Figure 1: Position of ligand 1

inside the binding site of the 5HT2Areceptor seen from the extracellularside (left) and the receptor-bindingsite simplified view showing a firstbinding pocket in yellow, a secondbinding pocket in green and Asp155 together with Asn 343 in red(right).



18–27. Docking analysis reports common interactions,already observed in ligands 1–5. Halogen substituents fitinto the receptor-binding pocket formed by Trp 151, Ile152, Leu 229, Ala 230, Phe 234, and Val 235, without ste-ric hindrance. This environment, rich with non-polar aminoacid residues, form a number of hydrophobic interactionswith the head part of the ligand and in that way stabilizesthe receptor–ligand complex (Figure 3). To further supportthis claim, AlogP of ligands (1–5 and 18–27) was calcu-lated and correlated with their affinity, and the obtainedresult of r = 0.75 indicates reasonable correlation (TableS1).

Ligand set 4 (compounds 28–30) (34): ligands 28–30include the sulfur atom in the head ligand part (Table 1).Addition of a sulfur atom has a negative influence onligand affinity, because of its size. Ligands 29 and 30 havereduced affinity, compared with ligand 28, because of thesteric clash of sulfur bulk with Val 347 and the reducedoverall hydrophobicity of the molecule.

The described interactions should be universal for allligands sharing common arylpiperazine structures. In orderto test this claim, docking analysis of eight arylpiperazineligands found in literature was performed (Table 2).

Tested ligands were docked into 5HT2A receptor, as flexi-ble ligand, rigid receptor system. Docking results are sum-marized in Table 2 and Figure 4.

Ligands 31–38a binding to the 5HT2A receptor can besummarized as follows: short salt bridge with Asp 155 andcorrect orientation of the ligand tail part, aromatic interac-tions with Trp 336, Phe 339, and Tyr 370, head of theligands interacts with Asn 343 and Phe.

To validate the obtained model of 5HT2A, we used acustom binary database formed of 40 compounds(20 active and 20 inactive) retrieved from ChEMBL data-base.a Selection criteria was the following: active ligands:5HT2A activity Ki range from 0.06 to 183 nM, arylpiperazine

Figure 4: Schematic presentationof docking results forarylpiperazines 32, 33, 37, and 38:ligand 32 (upper left), 33 (upperright), 37 (lower left), and 38 (lowerright). Observed interactions areshown as lines.


Sencanski et al.

substructure, at least one functional group capable offorming a hydrogen bond, and inactive ligands: 5HT2AKi > 1000 nM, with diverse chemical structures (Supple-mentary Data S1).

Rigid receptor and flexible ligand docking run was exe-cuted. To facilitate the docking process, the following con-straints were introduced as follows: short salt bridge withAsp 155 and correct orientation of the ligand tail part intothe hydrophobic-binding site pocket as the minimum inter-actions requirement for active ligands. In that way, inactiveligands were screened out.

Conclusions

The proposed model of the 5HT2A receptor can explainexperimental results of selected arylpiperazine ligands.Tested against a broader selection of different ligands,the 5HT2A model successfully differentiates betweenactive and inactive substances, based on shape and size.Due to software limitations, the results cannot beobtained automatically; the final result analysis must beperformed by a scientist. With careful examination ofdocking results, paying attention to key interactions, theproposed model can be used to elucidate the binding ofthe 5HT2A ligands.

Docking analysis results suggest that there are two distinctbinding pockets in the receptor-binding site with Asp 155located in its center. The first binding pocket consists ofLeu 123, Ser 159, Trp 336, Phe 339 Val 366, and Tyr 370located deep in the receptor cavity, and the secondformed by Trp 151, Ile 152, Leu 229, Ala 230, Phe 234,and Val 235 positioned closer to the receptor surface.

All the investigated ligands share a number of key interac-tions. The interaction responsible for ligand binding andcorrect orientation inside the binding site is the salt bridgewith Asp 155 together with a hydrogen bond with Asn343. The tail part of the ligand forms a number of aromaticinteractions with Leu 123, Trp 336, Phe 339, Val 366, andTyr 370, while the head part interacts with Trp 151, Ile152, Leu 229, Ala 230, Phe 234, and Val 235. Edge-to-face interactions are possible with Trp 336, Phe 339, andTyr 370 amino acid residues in the first binding pocket.Ligands that have groups capable of forming hydrogenbonds in their tail part can form additional hydrogen bondswith Ser 159 and/or Tyr 370. The size of the tail part is notlimiting, because both big and small substituents up to thesize of naphthyl are well tolerated. The second bindingpocket is predominantly hydrophobic in nature. Apart fromAsn 343, which can form a hydrogen bond with the ligand,all other amino acid residues are non-polar (Trp 151, Ile152, Leu 229, Ala 230, Phe 234, and Val 235). Ligandswith a hydrophobic head part benefit from those inter-actions and have increased affinity. On the other hand,ligands with bulk substituents are a lot less tolerated in the

second binding pocket and have their affinity reduced.There is a general correlation between lipophilicity of thedescribed ligands (AlogP) and their affinity toward 5HT2A.

Acknowledgments

This research was part of project 172032 funded by theMinistry of Education and Science, Republic of Serbia.

Conflict of Interest

All authors deny financial, commercial, or any other conflictof interest.

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Notes

aEuropean Bioinformatics Institute database (2013) https://www.ebi.ac.ukbhttp://www.ncbi.nlm.nih.gov/cACD/ChemSketch Freeware, version 11.00, AdvancedChemistry Development, Inc., Toronto, ON, Canada,www.acdlabs.com, 2004–2007.dhttp://avogadro.openmolecules.net/wiki/Main_Page

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Supporting Information

Additional Supporting Information may be found in theonline version of this article:

Figure S1. Plot of potential energy during productionphase.

Figure S2. Ramanchandran plot of constructed 5HT2Amodel.

Figure S3. Calculated ESP, showing distribution of posi-tive (red) and negative (blue) ESP for ligands 1, 2, 3 and 6.Negative ESP located in the center of tail aryl ring isrequired for ETF interactions.

Table S1. Calculated AlogP values for selected ligands,containing halogen atom in the head part.

Appendix S1. Custom binary database formed of 40compounds (20 active and 20 inactive) retrieved fromChEMBL database.



Molecular Modeling of 5HT 2A Receptor - Arylpiperazine Ligands...

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