Challenges and Opportunities in Central Nervous System Drug Discovery

Danon, Jonathan J.; Reekie, Tristan A.; Kassiou, Michael

doi:10.1016/j.trechm.2019.04.009

Cited by 59 publications

(49 citation statements)

References 99 publications

(112 reference statements)

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“…All rights reserved potential agents are identified, further studies are needed to determine the efficacy and optimal treatment conditions for each compound. Additionally, modifications through medicinal chemistry may be required to permit these compounds to enter the CNS [135].…”

Section: Accepted Articlementioning

confidence: 99%

Mechanisms of viral persistence in the brain and therapeutic approaches

Nath

Johnson

2021

The FEBS Journal

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There is growing recognition of the diversity of viruses that can infect the cells of the central nervous system (CNS). While the majority of CNS infections are successfully cleared by the immune response, some viral infections persist in the CNS. As opposed to resolved infections, persistent viruses can contribute to ongoing tissue damage and neuroinflammatory processes. In this manuscript we provide an overview of the current understanding of factors that lead to viral persistence in the CNS including how viruses enter the brain, how these pathogens evade antiviral immune system responses, and how viruses survive and transmit within the CNS. Further, as the CNS may serve as a unique viral reservoir, we examine the ways in which persistent viruses in the CNS are being targeted therapeutically.

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Section: Accepted Articlementioning

confidence: 99%

Mechanisms of viral persistence in the brain and therapeutic approaches

Nath

Johnson

2021

The FEBS Journal

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“…Here, only five hit compounds were in accordance with this rule (Table 5); therefore, the five compounds can be considered as potential drug candidates. One of the major challenges facing drug discovery for disorder of the central nervous system (CNS) is the presence of blood-brain barrier (BBB) that restricts the flow of molecules to the brain (Danon et al 2019). Significant properties such as polar surface area (PSA) and QlogBB are considered for a drug to be CNS leading candidates.…”

Section: Adme/toxmentioning

confidence: 99%

In silico molecular studies of natural compounds as possible anti-Alzheimer’s agents: ligand-based design

Iwaloye

Elekofehinti

Momoh

et al. 2020

Netw Model Anal Health Inform Bioinforma

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Alzheimer disease (AD) is the most common form of dementia contributing to about 60-70% of cases. β-Site amyloid precursor protein cleaving enzyme-1 (BACE1) plays an important role in the onset of AD and has become one of the important drug targets for AD. This approach has led to the development of promising BACE1 inhibitors, many of which are going through different phases of clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new drugs to uncover the mystery behind AD. This study focused on virtual screening of ~ 33,000 natural compounds to find potential BACE1 inhibitors. Multiple ligands pharmacophore model was generated using PHASE to screen retrieved compounds against a four-site (ADDR) hypothesis. Molecular docking was performed to predict the binding status of the natural compounds. Based on binding affinity, the top eight compounds were chosen for further analysis. The docked complexes were analyzed for binding free energy using PRIME MM/GBA calculation. The compounds were filtered for drug-likeness using ADME/TOX (absorption, distribution, metabolism, excretion and toxicity) prediction. AutoQSAR (automated quantitative structure activity relationship) was used to build a model for the prediction of compounds bioactivities. Despite retrieving a large number of compounds with favorable binding affinity, only a few were selected to be promising based on their ADME/TOX proprieties, binding free energy and predicted pIC 50. This study identified four natural compounds (NPC469686, NPC262328, NPC29763 and NPC86744) as novel BACE1 inhibitors. The insights obtained from this study could be employed to produce next-generation drug for AD.

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“…Traditional treatments for central nervous system disorders have shown limits and challenges. [ 1–3 ] Alternative ways to outperform current state‐of‐the‐art technologies are required in neuroscience, especially for neuronal regeneration [ 4,5 ] and electrical sensing/recording. [ 6 ] Despite a lot of efforts have been made to develop implantable neuronal devices (e.g., electrodes for deep brain stimulation, [ 7 ] retinal implants, [ 8,9 ] peripheral nerve stimulators, [ 10 ] and intracranial electrodes for diagnostic purposes [ 11 ] ), further research is needed to design an ideal neuronal interface embracing a combination of electrical conductivity and flexibility/lightness, together with high biocompatibility.…”

Section: Introductionmentioning

confidence: 99%

Hydrogenated Graphene Improves Neuronal Network Maturation and Excitatory Transmission

et al. 2021

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Traditional treatments for central nervous system disorders have shown limits and challenges. [1-3] Alternative ways to outperform current state-of-the-art technologies are required in neuroscience, especially for neuronal regeneration [4,5] and electrical sensing/recording. [6] Despite a lot of efforts have been made to develop implantable neuronal devices (e.g., electrodes for deep brain stimulation, [7] retinal implants, [8,9] peripheral nerve stimulators, [10] and intracranial electrodes for diagnostic purposes [11]), further research is needed to design an ideal neuronal interface embracing a combination of electrical conductivity and flexibility/lightness, together with high biocompatibility. Graphene has attracted considerable attention due to its outstanding properties, [12-17] such as high electrical and thermal conductivity, mechanical strength, ultra-thinness, and biocompatibility, opening new Graphene is regarded as a viable bio-interface for neuroscience due to its biocompatibility and electrical conductivity, which would contribute to efficient neuronal network signaling. Here, monolayer graphene grown via chemical vapor deposition is treated with remote hydrogen plasma to demonstrate that hydrogenated graphene (HGr) fosters improved cell-to-cell communication with respect to pristine graphene in primary cortical neurons. When transferred to polyethylene terephthalate, HGr exhibits higher wettability than graphene (water contact angle of 83.7° vs 40.7°), while preserving electrical conductivity (≈3 kΩ □-1). A rich and mature network is observed to develop onto HGr. The intrinsic excitability and firing properties of neurons plated onto HGr appears unaltered, while the basic passive and active membrane properties are fully preserved. The formation of excitatory synaptic connections increases in HGr with respect to pristine graphene, leading to a doubled miniature excitatory postsynaptic current frequency. This study supports the use of hydrogenation for tailoring graphene into an improved neuronal interface, indicating that wettability, more than electrical conductivity, is the key parameter to be controlled. The use of HGr can bring about a deeper understanding of neuronal behavior on artificial bio-interfaces and provide new insight for graphene-based biomedical applications.

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Challenges and Opportunities in Central Nervous System Drug Discovery

Cited by 59 publications

References 99 publications

Mechanisms of viral persistence in the brain and therapeutic approaches

Mechanisms of viral persistence in the brain and therapeutic approaches

In silico molecular studies of natural compounds as possible anti-Alzheimer’s agents: ligand-based design

Hydrogenated Graphene Improves Neuronal Network Maturation and Excitatory Transmission

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