Phenotypic approaches for CNS drugs DOI Creative Commons

Rakesh Sharma,

Caitlin R. M. Oyagawa, Hamid Abbasi

et al.

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(11), P. 997 - 1017

Published: Oct. 21, 2024

Central nervous system (CNS) drug development is plagued by high clinical failure rate. Phenotypic assays promote translation of drugs reducing complex brain diseases to measurable, clinically valid phenotypes. We critique recent platforms integrating patient-derived cells, which most accurately recapitulate CNS disease phenotypes, with higher throughput models, including immortalized balance validity and scalability. These were screened conventional commercial chemogenomic compound libraries. explore emerging library curation strategies improve hit rate quality, screening novel fragment libraries as alternatives, for more tractable target deconvolution. The relevant models used in these could harbor important, unidentified targets, so we review evolving agnostic deconvolution approaches, chemical proteomics artificial intelligence (AI), aid phenotypic mechanism elucidation, thereby facilitating rational hit-to-drug optimization.

Language: Английский

Positional scanning of natural product hispidol’s ring-B: discovery of highly selective human monoamine oxidase-B inhibitor analogues downregulating neuroinflammation for management of neurodegenerative diseases DOI Creative Commons
Ahmed H.E. Hassan, Hyeon Jeong Kim, Min Sung Gee

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 768 - 780

Published: Feb. 23, 2022

Multifunctional molecules might offer better treatment of complex multifactorial neurological diseases. Monoaminergic pathways dysregulation and neuroinflammation are common convergence points in diverse neurodegenerative neuropsychiatric disorders. Aiming to target these diseases, polypharmacological agents modulating both monoaminergic neuroinflammatory were addressed. A library analogues the natural product hispidol was prepared evaluated for inhibition monoamine oxidases (MAOs) isoforms. Several emerged as selective potential MAO B inhibitors. The most promising compounds further

Language: Английский

Citations

16
Levetiracetam Attenuates Adolescent Stress-induced Behavioral and Electrophysiological Changes Associated With Schizophrenia in Adult Rats DOI Creative Commons

Andreza M Cavichioli,

Thamyris Santos‐Silva, Anthony A. Grace

et al.

Schizophrenia Bulletin, Journal Year: 2022, Volume and Issue: 49(1), P. 68 - 77

Published: Aug. 21, 2022

Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates release neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits E/I balance. tested whether attenuate stress-induced changes, vHip hyperactivity, VTA adult rats.Male Sprague-Dawley subjected to combination daily footshock (postnatal day [PD] 31-40), three 1 h-restraint sessions (at PD31, 32, 40). In adulthood (PD62), animals anxiety responses (elevated plus-maze light-dark box), social interaction, cognitive function (novel object recognition test). The pyramidal neurons was recorded.Adolescent produced anxiety-like impaired sociability function. Levetiracetam (10 mg/kg) reversed these changes. increased neuron population firing rate induced by stress.These findings suggest attenuates adverse outcomes schizophrenia caused adolescence.

Language: Английский

Citations

14
Bioinformatics Perspective of Drug Repurposing DOI

Binita Patel,

Brijesh Gelat, Mehul N. Soni

et al.

Current Bioinformatics, Journal Year: 2024, Volume and Issue: 19(4), P. 295 - 315

Published: May 1, 2024

Abstract: Different diseases can be treated with various therapeutic agents. Drug discovery aims to find potential molecules for existing and emerging diseases. However, factors, such as increasing development cost, generic competition due the patent expiry of several drugs, increase in conservative regulatory policies, insufficient breakthrough innovations impairs new drugs learning productivity pharmaceutical industries. repurposing is process finding applications already approved, withdrawn from use, abandoned, experimental drugs. another method that may partially overcome hurdles related drug hence appears a wise attempt. being not standard process, leads administrative concerns problems. The also requires expensive, high-risk clinical trials establish safety efficacy repurposed drug. Recent field bioinformatics accelerate studies by identifying targets along candidate screening refinement. advancements comprehensive high throughput data genomics, epigenetics, chromosome architecture, transcriptomic, proteomics, metabolomics contribute understanding molecular mechanisms involved drug-target interaction. present review describes current scenario application bioinformatic tools identification

Language: Английский

Citations

2
Repositioning of receptor tyrosine kinase inhibitors DOI
Heba M. Mansour, Aiman S. El‐Khatib

Elsevier eBooks, Journal Year: 2023, Volume and Issue: unknown, P. 353 - 401

Published: Jan. 1, 2023

Language: Английский

Citations

5
NMDA glutamate receptor antagonist MK‐801 induces proteome changes in adult human brain slices which are partially counteracted by haloperidol and clozapine DOI
Valéria de Almeida, Niele Dias Mendes, Giuliana S. Zuccoli

et al.

Journal of Neurochemistry, Journal Year: 2024, Volume and Issue: 168(3), P. 238 - 250

Published: Feb. 8, 2024

Deciphering the molecular pathways associated with N-methyl-D-aspartate receptor (NMDAr) hypofunction and its interaction antipsychotics is necessary to advance our understanding of basis schizophrenia, as well capacity treat this disease. In regard, development human brain-derived models that are amenable studying neurobiology schizophrenia may contribute filling gaps left by widely employed animal models. Here, we assessed proteomic changes induced NMDA glutamate antagonist MK-801 on brain slice cultures obtained from adult donors submitted respective neurosurgery. Initially, demonstrated diminishes signaling in slices culture. Next, using mass-spectrometry-based proteomics systems biology silico analyses, found led alterations proteins related several previously pathophysiology, including ephrin, opioid, melatonin, sirtuin signaling, interleukin 8, endocannabinoid, synaptic vesicle cycle. We also evaluated impact both typical atypical MK-801-induced proteome changes. Interestingly, antipsychotic clozapine showed a more significant counteract protein NMDAr than haloperidol. Finally, dataset, identified potential modulators changes, which be considered promising targets schizophrenia. This dataset publicly available helpful further studies aimed at evaluating effects brain.

Language: Английский

Citations

1
One Path, Two Solutions: Network-Based Analysis Identifies Targetable Pathways for the Treatment of Comorbid Type II Diabetes and Neuropsychiatric Disorders DOI Creative Commons
Anna Onisiforou, Panos Zanos

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 3610 - 3624

Published: Oct. 10, 2024

Language: Английский

Citations

1
Integrated bioinformatics and interaction analysis to advance chronotherapies for mental disorders DOI Creative Commons
Apoorva Bhatnagar,

Gupta Raj,

Sandip Das

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Dec. 5, 2024

Robust connections have been identified between the pathophysiology of mental disorders and functioning circadian system. The overarching objective this study was to investigate potential for rhythms be leveraged therapeutics in disorders.

Language: Английский

Citations

1
Precision Psychiatry: Machine Learning as a Tool to Find New Pharmacological Targets DOI
João Rema, Filipa Novais, Diogo Telles‐Correia

et al.

Current Topics in Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 22(15), P. 1261 - 1269

Published: Oct. 5, 2021

The present work reviews current evidence regarding the contribution of machine learning to discovery new drug targets.Scientific articles from PubMed, SCOPUS, EMBASE, and Web Science Core Collection published until May 2021 were included in this review.The most significant areas research are schizophrenia, depression anxiety, Alzheimer´s disease, substance use disorders. ML techniques have pinpointed target gene candidates pathways, molecular substances, several biomarkers psychiatric Drug repositioning studies using identified multiple as promising therapeutic agents.Next-generation subsequent deep may power findings pharmacological agents by bridging gap between biological data chemical information.

Language: Английский

Citations

7
In silico screening of drug Bank data base to PDE10: A drug repurposing approach DOI Open Access

M. Gonzalo,

Galeana-Ascencio Ricardo,

Anaya-Ruiz Maricruz

et al.

GSC Biological and Pharmaceutical Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 010 - 021

Published: Sept. 4, 2023

Drug repurposing has emerged as a promising strategy for expediting drug development by identifying new therapeutic applications existing drugs. In this study employed in silico screening approach to explore the DrugBank database potential phosphodiesterase 10 (PDE10) inhibitors with neurological, psychiatric disorders and cancer treatment. PDE10 plays crucial role regulating cyclic nucleotide levels brain been implicated various diseases, including schizophrenia, Parkinson’s, Huntington’s certain types of cancer. Through molecular docking, we evaluated interactions energetics 28 candidate PDE10. Notably, 17 candidates met all selection criteria, presenting excellent further investigation. The theoretical demonstrated favorable ADMETx properties, their adverse effects were comparable or lower than controls. These findings indicate viability drugs, such Nebivolol, Fluvastatin, Pioglitazone others, inhibition diverse pathologies. Validation these preclinical studies may open avenues clinical applications, addressing unmet medical needs

Language: Английский

Citations

2
Network vaccinology DOI
Rachel Creighton, Viviane Schuch, Alysson H. Urbanski

et al.

Seminars in Immunology, Journal Year: 2020, Volume and Issue: 50, P. 101420 - 101420

Published: Aug. 1, 2020

Language: Английский

Citations

4