Novel inhibitors of Rho-kinase mediated neuroinflammatory pathways and their potential application in recovery of injured spinal cord

Nimgampalle, Mallikarjuna; Banavath, Hemanth Naick; Chakravarthy, Harshini; Saxena, Ambrish; Devanathan, Vasudharani

doi:10.1080/07391102.2019.1686066

Cited by 6 publications

(8 citation statements)

References 56 publications

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“…Proteins (6M71 and 6SVB) with sequence break were subjected to homology modeling using the swissMODEL server (Daina et al, 2017), subsequently used for further studies. Liganded form of protein (6LU7) were identified, retrieved, and employed for validation of docking (Nimgampalle et al, 2019). While non-liganded forms of proteins (6M71, 6VSB, 6VW1, 6VXS, and 6W4B) were subjected to active site prediction using the CASTp server (Tian et al, 2018).…”

Section: Selective Proteins and Enzymes Of Sars-cov-2 As Drug Targetsmentioning

confidence: 99%

Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets

Nimgampalle

Devanathan

Saxena

2020

Journal of Biomolecular Structure and Dynamics

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Recently Chloroquine and its derivative Hydroxychloroquine have garnered enormous interest amongst the clinicians and health authorities' world over as a potential treatment to contain COVID-19 pandemic. The present research aims at investigating the therapeutic potential of Chloroquine and its potent derivative Hydroxychloroquine against SARS-CoV-2 viral proteins. At the same time screening was performed for some chemically synthesized derivatives of Chloroquine and compared their binding efficacy with chemically synthesized Chloroquine derivatives through in silico approaches. For the purpose of the study, some essential viral proteins and enzymes were selected that are implicated in SARS-CoV-2 replication and multiplication as putative drug targets. Chloroquine, Hydroxychloroquine, and some of their chemically synthesized derivatives, taken from earlier published studies were selected as drug molecules. We have conducted molecular docking and related studies between Chloroquine and its derivatives and SARS-CoV-2 viral proteins, and the findings show that both Chloroquine and Hydroxychloroquine can bind to specific structural and non-structural proteins implicated in the pathogenesis of SARS-CoV-2 infection with different efficiencies. Our current study also shows that some of the chemically synthesized Chloroquine derivatives can also potentially inhibit various SARS-CoV-2 viral proteins by binding to them and concomitantly effectively disrupting the active site of these proteins. These findings bring into light another possible mechanism of action of Chloroquine and Hydroxychloroquine and also pave the way for further drug repurposing and remodeling.

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Section: Selective Proteins and Enzymes Of Sars-cov-2 As Drug Targetsmentioning

confidence: 99%

Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets

Nimgampalle

Devanathan

Saxena

2020

Journal of Biomolecular Structure and Dynamics

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“…Ng et al demonstrated that the subcellular localization of ZIKV NS5 in the nucleus is associated with its role in the modulation of the host immune response 71 . Coincidentally, it has been found that ROCK2 is involved in neuroin ammation and cell death by regulating the secretion of in ammatory cytokines such as tumor necrosis factor-alpha (TNFα/TNF), interleukin-1 beta (IL-1b), interleukin-2 (IL-2), and CXC chemokines 72 .…”

Section: Discussionmentioning

confidence: 99%

Mapping of Zika virus-host protein-protein interactions using yeast two-hybrid system and identification of re-purposed drug targets

Komarasamy,

Adnan,

Balasubramaniam

2024

Preprint

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Zika virus (ZIKV) garnered global attention over the past decade as outbreaks of the disease were linked to neurological complications. There are currently no antiviral drugs or vaccines with proven efficacy. The identification of human proteins targeted by ZIKV is crucial for deciphering the host pathways hijacked by the virus to replicate, evade innate immunity, and induce neuropathogenesis. In our study, Y2H screening of 8 ZIKV proteins identified 85 interacting host factors. These host factors are primarily involved in immune and inflammatory responses, cell death, centrosome and cell cycle regulation, ubiquitin pathways, central nervous system (CNS) development and neurological disorders. Rho associated coiled-coil containing protein kinase 2 (ROCK2) was selected for further evaluation of its role in ZIKV infection. Immunofluorescence staining showed colocalization between ROCK2 and ZIKV NS5 in the cell nucleus, indicating the interaction likely contributes to viral replication via immune and inflammatory responses. Further siRNA knockdown of ROCK2 resulted in significant inhibition of ZIKV genome copy number. The ZIKV-host interactome was also used as a platform to identify druggable human proteins targeted by existing host-directed antiviral drugs. Taken together, findings of this study aid in improving the understanding of ZIKV pathogenesis and identifying potential therapeutic targets.

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“…As another derivative of quercetin, luteolin, a flavone compound gained from Cissus quadrangularis L. [Vitaceae], the blocked activity of caspase-1 and Rho-associated protein kinase 2 (ROCK2) that is involved in inflammatory processes of SCI [109]. Isorhamnetin, another quercetin derivative, promoted functional recovery in rats by activating Nrf2/heme oxygenase 1 (HO-1) pathway and thereby combating oxidative stress following SCI.…”

Section: Quercetin Derivatives Against Spinal Cord Injurymentioning

confidence: 99%

Quercetin Derivatives in Combating Spinal Cord Injury: A Mechanistic and Systematic Review

Fakhri

Gravandi

Abdian

et al. 2022

Life

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Spinal cord injury (SCI) possesses a complicated etiology. There is no FDA-approved treatment for SCI, and the majority of current interventions focus on reducing symptoms. During SCI, inflammation, oxidative stress, apoptosis, and autophagy are behind the secondary phase of SCI and cause serious consequences. It urges the need for providing multi-targeting agents, that possess lower side effects and higher efficacy. The plant secondary metabolites are multi-targeting agents and seem to provide new roads in combating diseases. Flavonoids are phytochemicals of continual interest to scientists in combating neurodegenerative diseases (NDDs). Flavonoids are being studied for their biological and pharmacological effects, particularly as antioxidants, anti-inflammatory agents, anti-apoptotic, and autophagy regulators. Quercetin is one of the most well-known flavonols known for its preventative and therapeutic properties. It is a naturally occurring bioactive flavonoid that has recently received a lot of attention for its beneficial effects on NDDs. Several preclinical evidence demonstrated its neuroprotective effects. In this systematic review, we aimed at providing the biological activities of quercetin and related derivatives against SCI. Detailed neuroprotective mechanisms of quercetin derivatives are also highlighted in combating SCI.

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Novel inhibitors of Rho-kinase mediated neuroinflammatory pathways and their potential application in recovery of injured spinal cord

Cited by 6 publications

References 56 publications

Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets

Screening of Chloroquine, Hydroxychloroquine and its derivatives for their binding affinity to multiple SARS-CoV-2 protein drug targets

Mapping of Zika virus-host protein-protein interactions using yeast two-hybrid system and identification of re-purposed drug targets

Quercetin Derivatives in Combating Spinal Cord Injury: A Mechanistic and Systematic Review

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