Intrinsic activity and comparative molecular dynamics of buspirone analogues at the 5-HT1A receptors

Strzelczyk, Anna; Jarończyk, Małgorzata; Chilmończyk, Zdzisław; Mazurek, Aleksander P.; Chojnacka-Wójcik, E; Sylte, Ingebrigt

doi:10.1016/j.bcp.2004.02.026

Cited by 18 publications

(26 citation statements)

References 39 publications

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“…An additional set of 40 5-HT 1A receptor ligands (arylpiperazines, indoles and tetralines; see the Supporting Information) with a putative binding mode proposed in the literature ,− ,,,− were docked to the top-scoring ensemble of pockets. The binding modes were analyzed using SIFt methodology. , …”

Section: Methodsmentioning

confidence: 99%

From Homology Models to a Set of Predictive Binding Pockets–a 5-HT_1A Receptor Case Study

Warszycki

Rueda

Mordalski

et al. 2017

J. Chem. Inf. Model.

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Despite its remarkable importance in the arena of drug design, serotonin 1A receptor (5-HT1A) has been elusive to the x-ray crystallography community. This lack of direct structural information not only hampers our knowledge regarding the binding modes of many popular ligands (including endogenous neurotransmitter – serotonin), but also limits the search for more potent compounds. In this paper we shed new light on the 3D pharmacological properties of the 5-HT1A receptor by using a ligand-guided approach (ALiBERO) grounded in the Internal Coordinate Mechanics (ICM) docking platform. Starting from a homology template and set of known actives, the method introduces receptor flexibility via Normal Mode Analysis and Monte Carlo sampling, to generate a subset of pockets that display enriched discrimination of actives from inactives in retrospective docking. Here, we thoroughly investigated the repercussions of using different protein templates and the effect of compound selection on screening performance. Finally, the best resulting protein models were applied prospectively in a large virtual screening campaign, in which two new active compounds were identified that were chemically distinct from those described in the literature.

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Section: Methodsmentioning

confidence: 99%

From Homology Models to a Set of Predictive Binding Pockets–a 5-HT_1A Receptor Case Study

Warszycki

Rueda

Mordalski

et al. 2017

J. Chem. Inf. Model.

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“…The molecular mechanisms and structural events that occur at the receptor leading to pre-and post-synaptic activity however are not understood. Additional information regarding these mechanisms is crucial for design of drugs that can act selectively at pre-or post-synaptic 5-HT 1A receptors (Strzelczyk et al, 2004).…”

Section: Limitations and Future Directionsmentioning

confidence: 99%

Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5‐HT_1A receptor agonist

Piškulić

Olver

Maruff³

et al. 2009

Human Psychopharmacology

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Semi-acute adjunct treatment with buspirone may be too short to be clinically efficacious in patients with schizophrenia. Intrinsic activation of 5-HT(1A) receptors by atypical antipsychotics may hinder the ability of buspirone to further improve cognitive functions. Buspirone did not affect clinical outcomes for this chronically ill group of patients being treated with atypical antipsychotic drugs.

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“…Most of the computational experiments done so far on GPCRs concerned ligand binding site identification and predictions of the ligand interaction modes for either qualitative or quantitative structure affinity/selectivity relationships and drug design (reviewed also in refs and −479). In contrast, very few computational studies have been aimed at investigating the structural changes induced by agonists into receptor portions more or less distal from the ligand binding site. ,,,,,,,,,,,,,, The results of these studies are reviewed in a separate section.…”

Section: 3 Computational Modeling Of Ligand−receptor Interactionsmentioning

confidence: 99%

Computational Modeling Approaches to Structure−Function Analysis of G Protein-Coupled Receptors

2005

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Intrinsic activity and comparative molecular dynamics of buspirone analogues at the 5-HT1A receptors

Cited by 18 publications

References 39 publications

From Homology Models to a Set of Predictive Binding Pockets–a 5-HT_1A Receptor Case Study

From Homology Models to a Set of Predictive Binding Pockets–a 5-HT_1A Receptor Case Study

Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5‐HT_1A receptor agonist

Computational Modeling Approaches to Structure−Function Analysis of G Protein-Coupled Receptors

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Intrinsic activity and comparative molecular dynamics of buspirone analogues at the 5-HT1A receptors

Cited by 18 publications

References 39 publications

From Homology Models to a Set of Predictive Binding Pockets–a 5-HT1A Receptor Case Study

From Homology Models to a Set of Predictive Binding Pockets–a 5-HT1A Receptor Case Study

Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5‐HT1A receptor agonist

Computational Modeling Approaches to Structure−Function Analysis of G Protein-Coupled Receptors

Contact Info

Product

Resources

About

From Homology Models to a Set of Predictive Binding Pockets–a 5-HT_1A Receptor Case Study

From Homology Models to a Set of Predictive Binding Pockets–a 5-HT_1A Receptor Case Study

Treatment of cognitive dysfunction in chronic schizophrenia by augmentation of atypical antipsychotics with buspirone, a partial 5‐HT_1A receptor agonist