Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Shah, Jitesh R.; Mosier, Philip D.; Roth, Bryan L.; Kellogg, Glen E.; Westkaemper, Richard B.

doi:10.1016/j.bmc.2009.08.016

Cited by 23 publications

(21 citation statements)

References 44 publications

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“…One major difference in the construction of our model is that we included an artificial intracellular loop 3 (ICL3), whereas this was omitted in the Bruno model. Others have also constructed homology models of the human β2 adrenoceptor with MODELLER 46, 47…”

Section: Resultsmentioning

confidence: 99%

Affinity of aporphines for the human 5-HT2A receptor: Insights from homology modeling and molecular docking studies

Pecic

Makkar

Chaudhary

et al. 2010

Bioorganic & Medicinal Chemistry

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Analogs of nantenine were docked into a modeled structure of the human 5-HT 2A receptor using ICM Pro, GLIDE and GOLD docking methods. The resultant docking scores were used to correlate with observed in vitro apparent affinity (K e ) data. The GOLD docking algorithm when used with a homology model of 5-HT 2A , based on a bovine rhodopsin template and built by the program MODELLER, gives results which are most in agreement with the in vitro results. Further analysis of the docking poses among members of a C1 alkyl series of nantenine analogs, indicate that they bind to the receptor in a similar orientation, but differently than nantenine. Besides an important interaction between the protonated nitrogen of the C1 alkyl analogs and residue Asp155, we identified Ser242, Phe234 and Gly238 as key residues responsible for the affinity of these compounds for the 5-HT 2A receptor. Specifically, the ability of some of these analogs to establish a H-bond with Ser242 and hydrophobic interactions with Phe234 and Gly238 appears to explain their enhanced affinity as compared to nantenine.

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Section: Resultsmentioning

confidence: 99%

Affinity of aporphines for the human 5-HT2A receptor: Insights from homology modeling and molecular docking studies

Pecic

Makkar

Chaudhary

et al. 2010

Bioorganic & Medicinal Chemistry

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“…Many H 4 R receptor ligands contain a N ‐methylpiperazine moiety, but also other basic cyclic amines are an alternative to N ‐methylpiperazines including azetidines, aminopyrrolidines and piperazines (Engelhardt et al ., ; Smits et al ., ; Istyastono et al ., 2011a). While H 1 R SAR studies show a preference for tertiary amines over secondary and primary amines (Shah et al ., ), N ‐methylation can be used as a subtle chemical switch to modulate H 3 R affinity (Smits et al ., ) and H 3 R/H 4 R selectivity (Lim et al ., ; Govoni et al ., ). Changing piperazine to a N ‐methylpiperazine (Smits et al ., ) increases H 3 R affinity while maintaining similar affinity for H 4 R, but changing immepip ( 23 ) into methimepip ( 24 ) (Lim et al ., ), or changing imbutamine ( 25 ) to N, N‐dimethylimbutamine ( 26 ) (Govoni et al ., ) increases H 3 R selectivity over H 4 R.…”

Section: Structural Chemogenomics Analyses Of (Hist)aminergic Ligand mentioning

confidence: 97%

A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design

Kooistra¹,

Kuhne²,

Esch³

et al. 2013

British J Pharmacology

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BACKGROUND AND PURPOSEChemogenomics focuses on the discovery of new connections between chemical and biological space leading to the discovery of new protein targets and biologically active molecules. G-protein coupled receptors (GPCRs) are a particularly interesting protein family for chemogenomics studies because there is an overwhelming amount of ligand binding affinity data available. The increasing number of aminergic GPCR crystal structures now for the first time allows the integration of chemogenomics studies with high-resolution structural analyses of GPCR-ligand complexes. EXPERIMENTAL APPROACHIn this study, we have combined ligand affinity data, receptor mutagenesis studies, and amino acid sequence analyses to high-resolution structural analyses of (hist)aminergic GPCR-ligand interactions. This integrated structural chemogenomics analysis is used to more accurately describe the molecular and structural determinants of ligand affinity and selectivity in different key binding regions of the crystallized aminergic GPCRs, and histamine receptors in particular. KEY RESULTSOur investigations highlight interesting correlations and differences between ligand similarity and ligand binding site similarity of different aminergic receptors. Apparent discrepancies can be explained by combining detailed analysis of crystallized or predicted protein-ligand binding modes, receptor mutation studies, and ligand structure-selectivity relationships that identify local differences in essential pharmacophore features in the ligand binding sites of different receptors. CONCLUSIONS AND IMPLICATIONSWe have performed structural chemogenomics studies that identify links between (hist)aminergic receptor ligands and their binding sites and binding modes. This knowledge can be used to identify structure-selectivity relationships that increase our understanding of ligand binding to (hist)aminergic receptors and hence can be used in future GPCR ligand discovery and design.

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“…An additional difference they found was the interaction of Ser114(3.39) with Asn460(7.45) and Asp73(2.50) in the active and inactive states, respectively. A H1R homology model based on the β2-adrenergic receptor has been reported to investigate the binding mode of AMDA (9-(aminomethyl)-9,10-dihydroanthracene) analogs [20]. Docking analysis suggested that AMDA analogs interact with Asp107(3.32) and their rings primarily bind to residues in TM5 and TM6.…”

Section: H1 Receptormentioning

confidence: 99%

Structure-based discovery and binding site analysis of histamine receptor ligands

Kingsford-Adaboh

Keserü

2016

Expert Opinion on Drug Discovery

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Introduction: Application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, we review the development of histamine receptors models and their application on drug discovery. Expert opinion: In our opinion, the application of atomistic histamine receptor models played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery, however our analysis also demonstrate that for building H3 and H4 receptor homology models other GPCRs may be more suitable as a template. For these receptors we envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

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Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Cited by 23 publications

References 44 publications

Affinity of aporphines for the human 5-HT2A receptor: Insights from homology modeling and molecular docking studies

Affinity of aporphines for the human 5-HT2A receptor: Insights from homology modeling and molecular docking studies

A structural chemogenomics analysis of aminergic GPCRs: lessons for histamine receptor ligand design

Structure-based discovery and binding site analysis of histamine receptor ligands

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