CNS & Neurological Disorders - Drug Targets - Online First

JNK3 is a specific isoform of c-Jun N-terminal kinase, mainly found in the brain, and is highly sensitive to stress-associated signals in the central nervous system. It has been reported that JNK3 plays a crucial role in neurite formation and cognition. During pathological states such as Alzheimer’s disease, cerebral ischemia, Traumatic brain injury (TBI), Parkinson’s disease, and epilepsy, it is found to be in a hyperactivated form. Hyperphosphorylation of amyloid precursor protein (APP) and tau leads to toxic Aβ42 and neurofibrillary tangles. Excess Aβ activates JNK3 signaling, causing neuronal loss. JNK3 also contributes to mitochondrial dysfunction, Oxidative stress, neuroinflammation, and apoptosis, driving AD progression.

This study aims to identify possible therapeutics based on their physicochemical, ADMET, toxicity, and drug-likeness properties. Moreover, we utilized Molecular docking and Molecular dynamics (MD) simulation to reveal possible inhibitors against JNK3.

Based on the highest binding affinity against JNK3, the best compounds, Myricetin and Kaempferol, were subjected to an MD simulation study. RMSD analysis indicated that the JNK3-Kampferol complex showed more stability; at the same time, myricetin formed more hydrogen bonds with JNK3. Moreover, both compounds exhibited favorable ADMET properties.

This study identified Kaempferol and myricetin as potential inhibitors that target JNK3 through molecular docking and MD simulation studies. Both compounds demonstrated favorable ADMET profiles, supporting their promise as safe, orally available drug candidates.

Therefore, Kaempferol and myricetin emerge as promising candidates for further investigations in both in vitro and in vivo studies to treat Alzheimer’s disease and other neurodegenerative disorders.

Epilepsy affects 1-2% of the world population. In about 30% of individuals with epilepsy, the etiology is unknown after ruling out genetic mutations, severe injury, and several other possible causes. In about 20-30% of epilepsy patients, anti-epileptic drugs fail to control the seizures. The general trend in epilepsy genetics research is towards an increasingly powerful genetic platform for investigating genomic sequence and structural variation. This pattern will inevitably result in a quick rate of genetics-related discoveries and have significant effects on our capacity to identify and forecast epilepsy and related illnesses. About one-third of epileptic patients do not receive enough seizure control from the current medications. To close this treatment gap, new alternatives are required. Since phenytoin, a commercially available antiepileptic medicine, has a significant adverse effect called hypoguasia, which results in a diminished sense of taste, coumarin may lessen this side effect in addition to its antiepileptic properties, which are supported by several in-silico and in-vitro studies.

The current study examined the potential anti-epileptic effects of coumarin using network pharmacology and in-vitro studies.

During the initial stage, information about the phytoconstituent and the target genes linked to epilepsy and Coumarin was collected from open-source databases and scholarly literature. These data were then analyzed to identify common targets between the phytoconstituent and epilepsy. A Protein-Protein Interaction (PPI) network was built using the Search Tool for Identifying Interacting Genes and Proteins (STRING) database based on these common targets. Then, the hub genes were identified according to the degree of connectedness by integrating the Protein-Protein Interaction (PPI) network into the Cytoscape software. The networks of disease, genes, and Coumarin were obtained by following the processes of network pharmacology. A cell line investigation included the Cytotoxicity Study (MTT assay), Ca²⁺ Expression assay, and Mitochondrial Membrane Potential (JC-1 dye).

In the intracellular Ca²⁺ expression assay, the intracellular Ca²⁺ rate was highly enhanced in the toxic group and moderately in the co-treatment of the poisonous and sample groups, suggesting the neuroprotective effect of coumarin-containing liposomes (Coumarosome) against the pentylenetetrazol (PTZ) induction on Epilepsy model. Also, a membrane potential dye (JC-1) ratio of pentylenetetrazol (PTZ)-treated cells was very low, 0.61 ± 0.12, whereas untreated cells showed a JC-1 ratio of 68.23 ± 36.37, respectively. It is suggested that coumarin-containing liposomes (Coumarosome) may have a better mitochondrial recovery rate. The evidence that this study exhibits antiepileptic activity comes from cell line research.

To investigate the possible molecular processes of coumarin, the current study combined network pharmacology with bioinformatics techniques as it may function as an anti-epileptic tool, and it contains the TAS2R38 gene, which is involved in the compound-target network of epilepsy during the initial stage. The prepared Coumarin-containing liposomes (Coumarosomes) were well dispersed. These observed results suggest the neuroprotective effect of coumarosomes against the PTZ induction or epilepsy model.

The obtained data demonstrate that coumarin efficiently suppresses epileptic effects produced by pentylenetetrazol (PTZ). Thus, coumarin-containing liposomes (Coumarosome) represent a high potential therapeutic value as an antiepileptic pharmaceutical agent for the treatment of epilepsy.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors are used in primary pharmacotherapy for numerous neurodegenerative conditions, providing their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, quinazoline derivatives have emerged as a compelling model for neurodegenerative disease treatment, showcasing promising pharmacological features. Their unique structural features and pharmacokinetic profiles have sparked interest in their potential efficacy and safety across diverse neurodegenerative disorders. The exposure of quinazoline derivatives as a potential therapeutic way underscores the imperative for continued research exploration. Their multifaceted mechanisms of action and ability to target various pathways implicated in neurodegeneration offer exciting prospects for developing novel, effective, and well-tolerated treatments. Further investigations into their pharmacological activities and precise therapeutic roles are essential to advance our understanding of neurodegenerative disease pathophysiology and promote the development of modern therapeutic strategies to address this critical medical challenge.

Quinazoline derivatives have gained eminent acetylcholinesterase (AChE) inhibitory activity. Their ability to effectively modulate AChE activity makes them promising candidates for treating neurological disorders, particularly Alzheimer's disease (AD). Their intricate molecular structures confer selectivity and affinity for AChE, offering potential for the development of novel therapeutic agents targeting cholinergic pathways. Hence, in this study, we designed, synthesized, and characterized a series of spiro[cycloalakane-1,2'-quinazoline derivatives (1-6) to assess their possible AChE inhibiting ability using docking into the active sites.

The AChE inhibitory potential of spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) was explored via docking studies of the AChE active site. The findings revealed significant inhibitory activity and highlighted the promising nature of these derivatives.

The synthesized spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) exhibited their notable potential as AChE inhibitors. The observed significant inhibitory activity suggested that these derivatives warrant further exploration as candidates for developing therapeutic agents in AChE inhibitory pathways. This study emphasizes the relevance of quinazoline derivatives in searching for novel treatments for neurological disorders, particularly associated with cholinergic dysfunction, and they could be a useful alternative therapeutic agent.

Neuronal disorders have affected more than 15% of the world's population, signifying the importance of continued design and development of drugs that can cross the Blood-Brain Barrier (BBB).

BBB limits the permeability of external compounds by 98% to maintain and regulate brain homeostasis. Hence, BBB permeability prediction is vital to predict the activity of a drug-like substance.

Here, we report about developing BBBper (Blood-Brain Barrier permeability prediction) using machine learning tool.

A supervised machine learning-based online tool, based on physicochemical parameters to predict the BBB permeability of given chemical compounds was developed. The user-end webpage was developed in HTML and linked with back-end server by a python script to run user queries and results.

BBBper uses a random forest algorithm at the back end, showing 97% accuracy on the external dataset, compared to 70-92% accuracy of currently available web-based BBB permeability prediction tools.

The BBBper web tool is freely available at http://bbbper.mdu.ac.in.