Molecular Interaction Study of N1-p-fluorobenzyl-cymserine with TNF-α , p38 Kinase and JNK Kinase

Abstract

Alzheimer’s disease (AD) is an age-related neurodegenerative disease distinguished by progressive memory loss and cognitive decline. It is accompanied by classical neuropathological changes, including cerebral deposits of amyloid-beta peptide (Aβ) containing senile plaques, neurofibrillary tangles (NFTs) of phosphorylated tau (p-tau), and clusters of activated glial cells. Postmortem studies strongly support a critical role for neuroinflammation in the pathogenesis of AD, with activated microglia and reactive astrocytes surrounding senile plaques and NFTs. These are accompanied by an elevated expression of inflammatory mediators that further drives Ab and p-tau generation. Although epidemiological and experimental studies suggested that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may lessen AD risk by mitigating inflammatory responses, primary NSAID treatment trials of AD have not proved successful. Elevated systemic butyrylcholinesterase (BuChE) levels have been considered a marker of low-grade systemic inflammation, and BuChE levels are reported elevated in AD brain. Recent research indicates that selective brain inhibition of BuChE elevates acetylcholine (ACh) and augments cognition in rodents free of the characteristic undesirable actions of acetylcholinesterase-inhibitors (AChE-Is). Hence, centrally active BuChE-selective-inhibitors, cymserine analogs, have been developed to test the hypothesis that BuChE-Is would be efficacious and better tolerated than AChE-Is in AD. The focus of the current study was to undertake an in-silico evaluation of an agent to assess its potential to halt the self-propagating interaction between inflammation, Ab and p-tau generation. Molecular docking studies were performed between the novel BuChE-I, N1-p-fluorobenzyl-cymserine (FBC) and inflammatory targets to evaluate the potential of FBC as an inhibitor of p38, JNK kinases and TNF-α with respect to putative binding free energy and IC50 values. Our in-silico studies support the ability of FBC to bind these targets in a manner supportive of anti-inflammatory action that is subject to molecular dynamics and physiochemical studies for auxiliary confirmation.

Intracellular Signaling Pathways in Rheumatoid Arthritis

“…The approval of tofacitinib appears to have provided the impetus for future basic research aimed at discovering novel protein kinase-specific SMIs which may be targeted towards individual protein kinases or targeted as a dual protein kinase inhibitor such as the newly described N1-p-fluorobenzyl-cymserine which was reported to inhibit both p38 kinase and JNK as well as NF-κB [116]. …”

Biological evaluation of synthetic chalcone and flavone derivatives as anti-inflammatory agents

“…The elucidation of novel synthetic flavonoids of superior potency could be used to attenuate central nervous system inflammation (Phani et al ., 2012; Batool et al ., 2013; Pradhan and Andreasson, 2013) an otherwise significant contributor to chronic neurological/ cognitive decline associated with degenerative diseases such as Parkinson’s Disease. (Lopategui et al ., 2012).…”

“…In this study, we evaluated the efficacy of novel synthetic flavonoids and chalcones to inhibit pro-inflammatory processes in activated microglia cells exposed to bacterial lipopolysaccharide (LPS), a model commonly known to induce NF-kappaB transcriptional activation, iNOS, COX-2, TNF alpha, chemokine (C–C motif) ligand 2 (Hirai et al ., 2007; Furusawa et al ., 2009) and release of nitric oxide (NO) (Batool et al ., 2013; Wong, 2013). …”

Anti-inflammatory effects of thymoquinone in activated BV-2 microglial cells

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