Publications by authors named "Sairaj Satarker"

6 Publications

  • Page 1 of 1

In silico screening of neurokinin receptor antagonists as a therapeutic strategy for neuroinflammation in Alzheimer's disease.

Mol Divers 2021 Jul 31. Epub 2021 Jul 31.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.

Neuroinflammation is one of the detrimental factors leading to neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative disorders. The activation of microglial neurokinin 1 receptor (NK1R) by substance P (SP) enhances neuroinflammation which is mediated through pro-inflammatory pathways involving NFkB, ERK1/2, and P38 and thus projects the scope and importance of NK1R inhibitors. Emphasizing the inhibitory role of N Acetyl L Tryptophan (L-NAT) on NK1R, this is the first in silico screening of L-NAT mediated NK1R antagonism. In addition, FDA- approved ligands were screened for their potential NK1R antagonism. The L-NAT was docked in XP (Extra Precision) mode while FDA-approved ligands were screened in HTVS (High Throughput Virtual Screening), SP (Standard Precision), and XP mode onto NK1R (PDB:6HLO). The L-NAT and top 3 compounds FDA-approved ligands were subjected to molecular dynamics (MD) studies of 100 ns simulation time. The XP docking of L-NAT, indacaterol, modafinil and alosetron showed good docking scores. Their 100 ns MD showed brief protein-ligand interactions with an acceptable root mean square deviation. The protein-ligand contacts depicted pi-pi stacking, pi-cation, hydrogen bonds, and water bridges with the amino acids necessary for NK1R inhibition. The variable colour band intensities on the protein-ligand contact map indicated their binding strength with amino acids. The molecular mechanics/generalized born surface area (MM-GBSA) scores suggested favourable binding free energy of the complexes. Thus, our study predicted the ability of L-NAT, indacaterol, modafinil, and alosetron as capable NK1R inhibitors that can aid to curb neuroinflammation in conditions of AD which could be further ascertained in subsequent studies.
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http://dx.doi.org/10.1007/s11030-021-10276-6DOI Listing
July 2021

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy.

Postgrad Med 2021 Jun 16;133(5):489-507. Epub 2020 Dec 16.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India.

As the incidence of COVID-19 increases with time, more and more efforts are made to pave a way out for the therapeutic strategies to deal with the disease progression. Inflammation being a significant influencer in COVID-19 patients, it drives our focus onto the signaling cascades of the JAK/STAT pathway. JAK phosphorylation mediated by cytokine receptor activation leads to phosphorylation of STATs that translocate into the nucleus to translate for inflammatory mediators. The SARS-CoV-2 structural proteins like spike, nucleocapsid, membrane and envelope proteins along with the non- structural proteins 1-16 including proteases like 3CL  and PL promote its entry and survival in hosts. The SARS-CoV-2 infection triggers inflammation via the JAK/STAT pathway leading to recruitment of pneumocytes, endothelial cells, macrophages, monocytes, lymphocytes, natural killer cells and dendritic cells progressing towards cytokine storm. This produces various inflammatory markers in the host that determine the disease severity. The JAK/STAT signaling also mediates immune responses via B cell and T cell differentiation.With an attempt to reduce excessive inflammation, JAK/STAT inhibitors like Ruxolitinib, Baricitinib, Tofacitinib have been employed that mediate its actions via suppressors of cytokine signaling, cytokine inducible SH2 containing protein, Protein inhibitor of activated STAT and protein tyrosine phosphatases. Even though they are implicated with multiple adverse effects, the regulatory authorities have supported its use, and numerous clinical trials are in progress to prove their safety and efficacy. On the contrary, the exact mechanism of JAK/STAT inhibition at molecular levels remains speculative for which further investigations are required.
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http://dx.doi.org/10.1080/00325481.2020.1855921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784782PMC
June 2021

Involvement of the nervous system in COVID-19: The bell should toll in the brain.

Life Sci 2020 Dec 6;262:118568. Epub 2020 Oct 6.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, India. Electronic address:

The world is fuming at SARS-CoV-2 for being the culprit for causing the devastating COVID-19, claiming millions of lives across the globe in the form of respiratory disorders. But lesser known are its effects on the CNS that are slowly surfacing in the worldwide population. Our review illustrates findings that claim SARS-CoV-2's arrival onto the ACE2 receptors of neuronal and glial cells mainly via CSF, olfactory nerve, trigeminal nerve, neuronal dissemination, and hematogenous pathways. The role of SARS-CoV-2 structural proteins in its smooth viral infectivity of the host cannot be ignored, especially the spike proteins that mediate spike attachment and host membrane fusion. Worth mentioning the nucleocapsid, envelope, and membrane proteins make the proliferation of SARS-CoV-2 much simpler than expected in spreading infection. This has led to catastrophic conditions like seizures, Guillain-Barré syndrome, viral encephalitis, meningoencephalitis, acute cerebrovascular disease, and respiratory failures. Placing a magnifying lens on the lesser-explored CNS consequences of COVID-19, we attempt to shift the focus of our readers onto the new supporting threats to which further studies are needed.
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http://dx.doi.org/10.1016/j.lfs.2020.118568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537730PMC
December 2020

Zinc as a plausible epigenetic modulator of glioblastoma multiforme.

Eur J Pharmacol 2020 Nov 12;887:173549. Epub 2020 Sep 12.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104, India. Electronic address:

Glioblastoma Multiforme (GBM) is an aggressive brain tumor (WHO grade 4 astrocytoma) with unknown causes and is associated with a reduced life expectancy. The available treatment options namely radiotherapy, surgery and chemotherapy have failed to improve life expectancy. Out of the various therapeutic approaches, epigenetic therapy is one of the most studied. Epigenetic therapy is involved in the effective treatment of GBM by inhibiting DNA methyltransferase, histone deacetylation and non-coding RNA. It also promotes the expression of the tumor suppressor gene and is involved in the suppression of the oncogene. Various targets are being studied to implement proper epigenetic regulation to control GBM effectively. Zinc is one of the micronutrients which is considered to maintain epigenetic regulation by promoting the proper DNA folding, protecting genetic material from the oxidative damage and controlling the enzyme activation involved in the epigenetic regulation. Here, we are discussing the importance of zinc in regulating the epigenetic modifications and assessing its role in glioblastoma research. The discussion also highlights the importance of artificial intelligence using epigenetics for envisaging the glioma progression, diagnosis and its management.
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http://dx.doi.org/10.1016/j.ejphar.2020.173549DOI Listing
November 2020

Hydroxychloroquine in COVID-19: Potential Mechanism of Action Against SARS-CoV-2.

Curr Pharmacol Rep 2020 Aug 24:1-9. Epub 2020 Aug 24.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, 576104 India.

Purpose Of Review: The rapid spread of virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned out to be a global emergency. Symptoms of this viral infection, coronavirus disease 2019 (COVID-19), include mild infections of the upper respiratory tract, viral pneumonia, respiratory failure, multiple organ failure and death. Till date, no drugs have been discovered to treat COVID-19 patients, and therefore, a considerable amount of interest has been shown in repurposing the existing drugs.

Recent Findings: Out of these drugs, chloroquine (CQ) and hydroxychloroquine (HCQ) have demonstrated positive results indicating a potential antiviral role against SARS-CoV-2. Its mechanism of action (MOA) includes the interference in the endocytic pathway, blockade of sialic acid receptors, restriction of pH mediated spike (S) protein cleavage at the angiotensin-converting enzyme 2 (ACE2) binding site and prevention of cytokine storm. Unfortunately, its adverse effects like gastrointestinal complications, retinopathy and QT interval prolongation are evident in treated COVID-19 patients. Yet, multiple clinical trials have been employed in several countries to evaluate its ability in turning into a needed drug in this pandemic.

Summary: This review attempts to summarize the MOA of CQ/HCQ and its side effects. The existing literature hints that till date, the role of CQ/HCQ in COVID-19 may be sceptical, and further studies are warranted for obtaining a therapeutic option that could be effectively used across the world to rise out from this pandemic.
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http://dx.doi.org/10.1007/s40495-020-00231-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443392PMC
August 2020

Structural Proteins in Severe Acute Respiratory Syndrome Coronavirus-2.

Arch Med Res 2020 08 25;51(6):482-491. Epub 2020 May 25.

Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India. Electronic address:

What began with a sign of pneumonia-related respiratory disorders in China has now become a pandemic named by WHO as Covid-19 known to be caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The SARS-CoV-2 are newly emerged β coronaviruses belonging to the Coronaviridae family. SARS-CoV-2 has a positive viral RNA genome expressing open reading frames that code for structural and non-structural proteins. The structural proteins include spike (S), nucleocapsid (N), membrane (M), and envelope (E) proteins. The S1 subunit of S protein facilitates ACE2 mediated virus attachment while S2 subunit promotes membrane fusion. The presence of glutamine, asparagine, leucine, phenylalanine and serine amino acids in SARS-CoV-2 enhances ACE2 binding. The N protein is composed of a serine-rich linker region sandwiched between N Terminal Domain (NTD) and C Terminal Domain (CTD). These terminals play a role in viral entry and its processing post entry. The NTD forms orthorhombic crystals and binds to the viral genome. The linker region contains phosphorylation sites that regulate its functioning. The CTD promotes nucleocapsid formation. The E protein contains a NTD, hydrophobic domain and CTD which form viroporins needed for viral assembly. The M protein possesses hydrophilic C terminal and amphipathic N terminal. Its long-form promotes spike incorporations and the interaction with E facilitates virion production. As each protein is essential in viral functioning, this review describes the insights of SARS-CoV-2 structural proteins that would help in developing therapeutic strategies by targeting each protein to curb the rapidly growing pandemic.
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http://dx.doi.org/10.1016/j.arcmed.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247499PMC
August 2020
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