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Medicinal use of indole piperazine derivative

A use, piperidine technology, applied in the field of nervous system disease drugs, can solve the problem of not reflecting the real active conformation

Inactive Publication Date: 2014-08-13
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Traditional receptor structure-based drug design usually only relies on the X-ray structure of the receptor or homology modeling models, but due to the flexibility of proteins in vivo, a single receptor model cannot reflect the binding of receptors to all ligands true active conformation

Method used

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  • Medicinal use of indole piperazine derivative
  • Medicinal use of indole piperazine derivative
  • Medicinal use of indole piperazine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 5-HT 1A Receptor 3D model construction

[0027] The protein sequence is from the Swiss-Prot database (http: / / www.expasy.ch / sprot / ), human epinephrine β 2 receptors and 5-HT 1A The sequence numbers of the receptors are P07550 and P08908, respectively. Using the ClustalW algorithm in the FASTA program, the 5-HT 1A receptors and adrenergic beta 2 The sequences of the receptors were compared by multiple sequences, and then the matched sequences were fine-tuned according to the positions of the conserved residues in the GPCR superfamily. The results are shown in Table 1; 5-HT 1A receptors and adrenergic beta 2 The homology of receptor transmembrane helix is ​​41.9%.

[0028] Table 1 5-HT 1A receptors and adrenergic beta 2 Homology and similarity of seven transmembrane domains of receptors

[0029]

[0030] adrenaline beta2 Receptor (Rasmussen SGF, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, et al. Nature 2007; 450(7168): 383-U4. PDB number ...

Embodiment 25-HT1

[0031] Example 25-HT 1A Molecular Dynamics Simulation of Receptor Added Membrane

[0032] Molecular dynamics simulations were performed using GROMACS 3.3.1 and GROMOS96 force fields. 5-HT after initial energy optimization 1A The receptor model is inserted vertically into the POPC (palmitoyl-oleoyl-phosphatidylcholine) phospholipid bilayer. The protein and POPC structural models are dissolved in the single point charge (SPC) water molecule model; the Berendsen constant temperature method is used to maintain the system temperature at 300K; the system pressure is maintained at one atmospheric pressure; the LINCS algorithm is used to limit the bond length of all chemical bonds containing hydrogen atoms; Electrostatic interactions are calculated by the particle-mesh Ewald (PME) method to is the cutoff value (cut off); the cutoff value of the Lennard-Jones interaction is selected as For each simulation system, a cubic box is used as the simulation unit, the protein is placed i...

Embodiment 3

[0034] Embodiment 3 constructs 5-HT 1A Active site detection and dynamic pharmacophore modeling of receptors

[0035] The representative conformations of the first 10 clusters in the kinetic simulation results were taken as the receptor model, and the conserved Asp 3.32 around The in-scope regions are defined as boxes for site probing by the GRID program. Since the GPCR receptor pocket is negatively charged, four typical probes were selected: N+ (positive charge probe), O (hydrogen bond acceptor probe), N1 (hydrogen bond donor probe) and DRY (hydrophobic group probe). needles) to probe the corresponding electronegativity, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic chemical environment in the protein, respectively. According to the probe point obtained by superimposing 10 conformations of Cα, select the appropriate cluster according to the binding energy of the GRID probe point and the nature of the interaction with the receptor amino acid residue, and cal...

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Abstract

The invention belongs to the field of pharmacy, relates to medicinal use of an indole piperazine derivative, and in particular relates to appetency of the indole piperazine derivative to dopamine D3 receptor and 5-HT1A and 5-HT2A receptors, function characteristics and use in preparation of medicines for nervous system disease; adrenergic beta-2 receptor crystal structure is used as a template for the construction of a dopamine 5-HT1A receptor model; by accuracy verification on the receptor model and molecular dynamics simulation, a flexible receptor conformation can be obtained; active sites of the flexible receptor conformation can be detected; detection results are superimposed and a dynamic receptor effective-mass model is constructed; an existing compound database is screened and the activity is tested; and results show that the screened compound FDFWHF003 and its derivatives have good activity to the dopamine receptor and 5-HT receptors, can be used for preparation of anti-schizophrenia medicines, and especially is suitable for the preparation of medicines for treating schizophrenia caused by dopamine system and 5-HT system functional disorders.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to the medicinal use of indolepiperazine derivatives, in particular to the effect of indolepiperazine derivatives on dopamine D 3 receptors and 5-HT 1A , 5-HT 2A The affinity and action characteristics of the receptor and its application in the preparation of medicines for nervous system diseases, especially the field of medicines for nervous system diseases related to dopamine receptors and 5-HT receptors. Background technique [0002] Schizophrenia is a common persistent and chronic major mental illness, clinically manifested as positive symptoms and negative symptoms, the former includes hallucinations, delusions, chorea, etc.; the latter mainly refers to cognitive impairment, learning and memory impairment, working memory impairment, etc. With the continuous increase of people's work and life pressure, mental problems have serious adverse effects on the whole society. The early first-g...

Claims

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Application Information

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IPC IPC(8): A61K31/496A61K31/454A61P25/18
Inventor 付伟杜鹏
Owner FUDAN UNIV
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