H-3 Receptor Antagonist and JNK-3 Inhibitor: A new therapeutic approach to treat Parkinson’s disease

Ambhore, Nilesh Sudhakar; Mohire, Shubhashri; Kalidindi, Ramasatyanarayana Raju; Mulukutala, Shashank; Murthy, Vishakantha; Elango, K

doi:10.1016/j.parkreldis.2015.10.193

Cited by 3 publications

(2 citation statements)

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“…Upon activation, JNKs can interact with the pathway's final effectors, phosphorylate transcription factors, such as the transcription factor activator protein-1 (AP1) family proteins, c-JUN, activating transcription factors (ATF), and (ETS Like-1 protein) Elk1 [1]. Based on knockout experiments and its specific tissue expression, JNK3 has emerged as a promising target for potential treatments of neuroinflammation and neurodegenerative disorders like Huntington's disease [2][3][4], Parkinson's disease [5], and Alzheimer's disease [6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Identification of Potential JNK3 Inhibitors: A Combined Approach Using Molecular Docking and Deep Learning-Based Virtual Screening

Yao,

Shen,

Shen

et al. 2023

Pharmaceuticals

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JNK3, a member of the MAPK family, plays a pivotal role in mediating cellular responses to stress signals, with its activation implicated in a myriad of inflammatory conditions. While JNK3 holds promise as a therapeutic target for neurodegenerative disorders such as Huntington’s, Parkinson’s, and Alzheimer’s diseases, there remains a gap in the market for effective JNK3 inhibitors. Despite some pan-JNK inhibitors reaching clinical trials, no JNK-targeted therapies have achieved market approval. To bridge this gap, our study introduces a sophisticated virtual screening approach. We begin with an energy-based screening, subsequently integrating a variety of rescoring techniques. These encompass glide docking scores, MM/GBSA, and artificial scoring mechanisms such as DeepDock and advanced Graph Neural Networks. This virtual screening workflow is designed to evaluate and identify potential small-molecule inhibitors with high binding affinity. We have implemented a virtual screening workflow to identify potential candidate molecules. This process has resulted in the selection of ten molecules. Subsequently, these ten molecules have undergone biological activity evaluation to assess their potential efficacy. Impressively, molecule compound 6 surfaced as the most promising, exhibiting a potent kinase inhibitory activity marked by an IC50 of 130.1 nM and a notable reduction in TNF-α release within macrophages. This suggests that compound 6 could potentially serve as an effective inhibitor for the treatment of neuroinflammation and neurodegenerative diseases. The prospect of further medicinal modifications to optimize compound 6 presents a promising avenue for future research and development in this field. Utilizing binding pose metadynamics coupled with molecular dynamics simulations, we delved into the explicit binding mode of compound 6 to JNK3. Such insights pave the way for refined drug development strategies. Collectively, our results underscore the efficacy of the hybrid virtual screening workflow in the identification of robust JNK3 inhibitors, holding promise for innovative treatments against neuroinflammation and neurodegenerative disorders.

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Section: Introductionmentioning

confidence: 99%

Identification of Potential JNK3 Inhibitors: A Combined Approach Using Molecular Docking and Deep Learning-Based Virtual Screening

Yao,

Shen,

Shen

et al. 2023

Pharmaceuticals

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“…14 A growing body of literature also supports a role for H 3 R in influencing the release of a number of additional neurotransmitters like acetylcholine (Ach), dopamine (DA), glutamate, noradrenaline (NA) and serotonin (5-HT). [14][15][16] H3R are mainly located in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum and hypothalamus; however, the highest density of H3R are found in basal ganglia, 17,18 an important seat in the brain involved in coordination of information from sensorimotor, motivational and cognitive brain areas to control behaviors such as movement and reward learning. The selective antagonist/ inverse antagonist of H3R such as thioperamide (THP) and ciproxifan (CPX), 19 potentiate neurochemical and behavioral effects of haloperidol (HAL) and enhance the turnover of dopamine in midbrain of rats.…”

Section: Introductionmentioning

confidence: 99%

Determination of Histamine H3-Receptor Antagonist Conessine in Wistar Rat Plasma by a Rapid and Sensitive RP-UFLC Method: Application to a Pharmacokinetic Study

Ambhore¹,

Kalidhindi²,

Mohire³

et al. 2020

JYP

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Objectives: Epidemiological data suggests the highest density of histamine H3-receptors (H3R) in basal ganglia of central nervous system (CNS) wherein they function as inhibitory auto-receptors and control the release of many neurotransmitters. Inhibition of H3R increases the turnover of neurotransmitters, especially dopamine in basal ganglia and could be beneficial to treat Parkinson's disease. Methods: In this study, we formulated the brain targeting liposomes of conessine, a selective antagonist for H3R to increase bioavailability and developed and validated a rapid and sensitive reverse phase ultra-force liquid chromatographic (RP-UFLC) method and to quantitate conessine in Wistar rat plasma and tissue. Plasma and tissue samples were extracted by protein precipitation technique using acetonitrile (ACN) and aripiprazole as the internal standard. Chromatographic separation was performed on the Hibar C 18 column with a mobile phase of Hexane Sulphonic acid (10 mM, pH 10.0 adjusted with ammonia) and methanol at a flow rate of 0.9 ml/min. Results: The lower limit of quantification of the developed method was 4.0 ng/ml and 6.0 ng/g in plasma and tissue samples, respectively. Liposomes of conessine (equivalent to 20 mg/kg) administered orally to animals, demonstrated remarkable absorption into the systemic circulation with maximum concentration (~8700 ng/ ml) within 2.0 h. The order of area under curve was found to be kidney> brain> liver> lungs> spleen> heart. Conclusion: The liposomes of conessine were rapidly taken up into the brain and showed a good brain concentration after 2.0 h; sustenance up to 4.0 h was achieved which is better than conessine solution.

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Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases

Wang,

Lv,

Zhao

2023

Ageing Research Reviews

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H-3 Receptor Antagonist and JNK-3 Inhibitor: A new therapeutic approach to treat Parkinson’s disease

Cited by 3 publications

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Identification of Potential JNK3 Inhibitors: A Combined Approach Using Molecular Docking and Deep Learning-Based Virtual Screening

Identification of Potential JNK3 Inhibitors: A Combined Approach Using Molecular Docking and Deep Learning-Based Virtual Screening

Determination of Histamine H3-Receptor Antagonist Conessine in Wistar Rat Plasma by a Rapid and Sensitive RP-UFLC Method: Application to a Pharmacokinetic Study

Research on ferroptosis as a therapeutic target for the treatment of neurodegenerative diseases

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