Homology Modeling of the Serotonin 5-HT1A Receptor Using Automated Docking of Bioactive Compounds with Defined Geometry

Nowak, Mateusz; Kołaczkowski, Marcin; Pawłowski, Maciej; Bojarski, Andrzej J.

doi:10.1021/jm050826h

Cited by 93 publications

(84 citation statements)

References 38 publications

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“…29) A second interaction between the indole moiety and Phe 6.52 was also observed. These docking poses are highly consistent with the binding mode of longchain arylpiperazines proposed by Kołaczkowski et al and Nowack et al 30,31) Additionally, the indole moiety was oriented towards helices I, II and VII, in a favorable position to establish a π-π interaction with the aromatic ring of Tyr 2.54 at the end of helix II.…”

Section: Resultssupporting

confidence: 87%

Synthesis, 5-Hydroxytryptamine1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-Indole Derivatives

Pessoa‐Mahana

Núñez

Araya‐Maturana

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-hKey words indolylalkylarylpiperazine; 5-hydroxytryptamine 1A receptor; docking; binding; synthesis Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that mediates various physiological and pathological processes in the peripheral and central nervous system (CNS) by interacting with several different receptors.1-3) The 5-HT 1A receptor sub-population has attracted considerable attention in the drug discovery field.4-7) It is assumed that anxiolytic drugs such as buspirone (1), tandospirone (2), gepirone (3) or ipsapirone (4) (Fig. 1), exert their pharmacological activity through the activation of the 5-HT 1A receptor, where they act as partial agonists.8-10) The 5-HT 1A receptor is also implicated in many other physiopathological CNS processes and conditions such as neuroprotection, schizophrenia, Parkinson's and Alzheimer's diseases, acting alone or associated with other neurotransmitter receptors, especially dopamine receptors.Long-chain arylpiperazine derivatives are one of the most important classes of 5-HT 1A ligands. In general, the arylpiperazine moiety is a good template for drugs acting on many different biological targets, especially CNS receptors.11-13) As a consequence, many compounds containing this scaffold bind with high affinity at 5-HT 1A receptors, but only a few of them also show high selectivity for 5-HT 1A over other receptors. 14)Structure-activity relationship (SAR) studies, performed with numerous generations of arylpiperazine derivatives, showed that CNS activity and both, receptor affinity and selectivity depend basically on the N-1-aryl substituent and a terminal fragment bound to the N-4 atom of the piperazine moiety by an alkyl chain. In these studies, this alkyl spacer is frequently composed of two to four methylene units. 15,16) On the other hand, the indole substructure is the basic element in a large number of biologically active natural and synthetic products. In fact, until this day, the indole motif is present in more than 400 drugs and 3000 patents.17) The range of applications for these therapeutically relevant compounds includes anti-inflammatory drugs, protein kinase C inhibitors, 5-HT agonists and antagonists, melatonin agonists and glucocorticoid receptor modulators.18) Studies on structural modifications of indolylalkylarylpiperazines carried out by Heinrich et al. 14,19) reported a high-affinity pattern for 5-HT 1A agonism and succeeded in optimizing selectivity over dopamine D 2 receptors. This structural pattern considers a C5-substituted indole ring bearing different functional groups and a parasubstituted arylpiperazine. In these studies, a four-carbon atom chain was employed as a linker of both heterocyclic moieties. On the other hand, a few studies on indolylalkylarylpiperazines containing a propyl chain as a linker have been reported regarding their 5-HT 1B/1D receptor affinity. 20,21) However, the influence of a propylic connecting chain on the affinity of this type ...

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Section: Resultssupporting

confidence: 87%

Synthesis, 5-Hydroxytryptamine1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1H-Indole Derivatives

Pessoa‐Mahana

Núñez

Araya‐Maturana

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Since the determination of the inactive dark-state rhodopsin structure (18), a number of homology models of other class A GPCRs have been reported (66)(67)(68)(69)(70). Typically, homology models start by alignment of so-called fingerprint motifs that are common among the family.…”

Section: Comparison To Rhodopsin-based Gpcr Modelsmentioning

confidence: 99%

High-Resolution Crystal Structure of an Engineered Human β ₂ -Adrenergic G Protein–Coupled Receptor

Cherezov

Rosenbaum

Hanson

et al. 2007

Science

3,102

102

3,259

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G protein-coupled receptors comprise the largest family of eukaryotic signal transduction proteins that communicate across the membrane. We report the crystal structure of a human β 2 -adrenergic receptor-T4 lysozyme fusion protein bound to the partial inverse agonist carazolol at 2.4 Å resolution. The structure provides a high-resolution view of a human G protein-coupled receptor bound to a diffusible ligand. Ligand-binding site accessibility is enabled by the second extracellular loop which is held out of the binding cavity by a pair of closely spaced disulfide bridges and a short helical segment within the loop. Cholesterol, a necessary component for crystallization, mediates an intriguing parallel association of receptor molecules in the crystal lattice. Although the location of carazolol in the β 2 -adrenergic receptor is very similar to that of retinal in rhodopsin, structural differences in the ligand binding site and other regions highlight the challenges in using rhodopsin as a template model for this large receptor family.* To whom correspondence should be addressed: stevens@scripps.edu; kobilka@stanford.edu $ These authors contributed equally Author Contributions: RCS and BKK independently pushed the GPCR structural biology projects for more than 15 years. BKK managed the protein design, production and purification. RCS managed novel crystallization and data collection methods development and experiments. VC developed novel methods for, and performed LCP crystallization, LCP crystal mounting, LCP data collection, model refinement, analyzed the results, and was involved in manuscript preparation. DMR supplied protein materials for all crystallization trials, grew and collected data from the bicelle crystals, collected, processed and refined the 3.5 Å LCP structure, refined the 2.4 Å structure, analyzed the results, and was involved in manuscript preparation. MAH designed the blind crystal screening protocol and collected the 2.4 Å data set, processed the 2.4 Å data, solved the structure by MR at 3.5 Å and 2.4 Å resolution, wrote the initial draft of the manuscript and created all figures. SGFR assisted with the final stages of β 2 AR-T4L purification. FST expressed β 2 AR-T4L in insect cells and, together with TSK, performed the initial stage of β 2 AR purification. HJC assisted with the refinement. PK assisted in developing novel methods to screen the transparent crystals, data collection, refinement, and was involved in manuscript preparation. WIW assisted with low resolution data collection and processing, solved the β 2 AR-T4L molecular replacement problem at 3.5 Å, participated in the 2.4 Å refinement process, and participated in structure analysis and manuscript preparation. BKK additionally assisted with β 2 AR-T4L purification, β 2 AR-T4L 3.5 Å synchrotron data collection, structure analysis and manuscript preparation. BKK and DMR designed the β 2 AR-T4L fusion protein strategy. RCS additionally assisted with β 2 AR-T4L crystallization, 2.4 Å data collection, structure solution, refinem...

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“…An interaction with this residue was also demonstrated in the ligand binding of other aryl piperazine derivatives. 19 Then a bifurcated hydrogen bond is observed between the carbonyl oxygen atom and the amide group of Asn 386 (Asn 7.39). This is consistent with site directed mutagenesis data showing that the valine substitution for Asn 7.39 induces a reduction in the binding affinity of 5-HT 1A ligands.…”

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confidence: 99%

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

Liégeois

Lespagnard

Meneses‐Salas

et al. 2014

ACS Med. Chem. Lett.

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An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT 1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible reinforcement of this interaction to increase the affinity for 5-HT 1A receptors, different 4-substituted-phenyl analogues were synthesized and tested. The most important increase of affinity is obtained with two electron-donating methyl groups in positions 3 and 5. KEYWORDS: CH−π interaction, quinoxaline, carboxamide, arylpiperazine, electron-donating, docking R ecently, we reported that a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue was shown to be favorable compared to the corresponding 4-phenyl-piperazine one in terms of affinity for 5-HT 1A receptors in a series of 4-arylpiperazine-ethyl carboxamides. 1 An electrostatic interaction between the distal benzene ring of the molecule and a phenylalanine residue (Phe 6.52) particularly in the 5-HT 1A receptor binding pocket was suggested by molecular modeling approaches. 2 The almost coplanar orientation of both rings displayed in the 4-phenyl-THP compound appeared as an important spatial requirement for an optimal interaction with the 5-HT 1A receptor in the present series. This orientation should stabilize the ligand binding by an edge-to-face CH−π interaction between the phenyl ring of the 4-phenyl-THP compounds and the phenyl ring of the Phe 6.52 residue. 2 This would explain why the chemical modification of the piperazine ring into THP is favorable for receptor affinity.The electron donating/withdrawing properties of an aromatic substituent is an important factor for the electron density of the aromatic ring and consequently for the capacity of these rings to be involved in aromatic stacking interactions. 3 Some studies have already shown the impact of the electronic properties of the substituents on the stability of these interactions in ligand−receptor binding. 4,5 Therefore, by increasing the electronic density with an electron-donating group, we expected to reinforce the interaction between the distal benzene ring and the Phe 6.52 residue. The substituents were positioned either in position 4 or positions 3 and 5 of the distal ring in order to avoid a sterical constraint if present in position 2 or 6. To explore a possible opposite effect linked to the electronic properties of the substituents, electron-withdrawing atoms were also introduced. The THP derivatives were tested, in parallel with the corresponding arylpiperazine derivatives, for their affinity for 5-HT 1A receptors. The intrinsic activity of six selected compounds was also investigated using an electrophysiological approach.The target compounds were prepared by reaction of the appropriate primary amine with the appropriate acyl chloride (2-naphthoyl chloride or 2-quinoxaline chloride) as reported in Scheme 1. The crude amines were synthesized following a Gabriel pro...

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Homology Modeling of the Serotonin 5-HT_1A Receptor Using Automated Docking of Bioactive Compounds with Defined Geometry

Cited by 93 publications

References 38 publications

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

High-Resolution Crystal Structure of an Engineered Human β ₂ -Adrenergic G Protein–Coupled Receptor

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

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Homology Modeling of the Serotonin 5-HT1A Receptor Using Automated Docking of Bioactive Compounds with Defined Geometry

Cited by 93 publications

References 38 publications

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Synthesis, 5-Hydroxytryptamine<sub>1A</sub> Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

High-Resolution Crystal Structure of an Engineered Human β 2 -Adrenergic G Protein–Coupled Receptor

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT1A Receptors

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Homology Modeling of the Serotonin 5-HT_1A Receptor Using Automated Docking of Bioactive Compounds with Defined Geometry

High-Resolution Crystal Structure of an Engineered Human β ₂ -Adrenergic G Protein–Coupled Receptor

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors