On the Inhibitory Affect of Some Dementia Drugs on DNA Polymerase β Activity

Vyjayanti, Vaddadi N.; Chary, N. S.; Rao, K. S.

doi:10.1007/s11064-007-9587-3

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…In a completely surprising finding, Vijayanti and colleagues have reported that the dementia drugs donepezil hydrochloride, rivastigmine tartrate and Nootropil bind to the 8kDa domain of Polβ as determined in an in silico analysis to evaluate potential macromolecular docking sites on the protein [164]. Using in vitro DNA polymerase and 5’dRP lyase assays, they show no significant impact on polymerase activity but suggest that rivastigmine tartrate and Nootropil both have a significant impact on Polβ dependent 5’dRP lyase activity.…”

Section: Inhibition Of Polβ-dependent 5’drp Lyase Activity and The Cementioning

confidence: 99%

Targeting DNA Polymerase ß for Therapeutic Intervention

Goellner

Svilar²,

Almeida³

et al. 2012

CMP

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DNA damage plays a causal role in numerous disease processes. Hence, it is suggested that DNA repair proteins, which maintain the integrity of the nuclear and mitochondrial genomes, play a critical role in reducing the onset of multiple diseases, including cancer, diabetes and neurodegeneration. As the primary DNA polymerase involved in base excision repair, DNA polymerase β (Polβ) has been implicated in multiple cellular processes, including genome maintenance and telomere processing and is suggested to play a role in oncogenic transformation, cell viability following stress and the cellular response to radiation, chemotherapy and environmental genotoxicants. Therefore, Polβ inhibitors may prove to be effective in cancer treatment. However, Polβ has a complex and highly regulated role in DNA metabolism. This complicates the development of effective Polβ-specific inhibitors useful for improving chemotherapy and radiation response without impacting normal cellular function. With multiple enzymatic activities, numerous binding partners and complex modes of regulation from post-translational modifications, there are many opportunities for Polβ inhibition that have yet to be resolved. To shed light on the varying possibilities and approaches of targeting Polβ for potential therapeutic intervention, we summarize the reported small molecule inhibitors of Polβ and discuss the genetic, biochemical and chemical studies that implicate additional options for Polβ inhibition. Further, we offer suggestions on possible inhibitor combinatorial approaches and the potential for tumor specificity for Polβ-inhibitors.

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Section: Inhibition Of Polβ-dependent 5’drp Lyase Activity and The Cementioning

confidence: 99%

Targeting DNA Polymerase ß for Therapeutic Intervention

Goellner

Svilar²,

Almeida³

et al. 2012

CMP

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“…Moreover, the medications approved by the US FDA and other regulatory authorities incite adverse effects upon consumption [31,32]. These include DNA polymerase damage [33], developmental retardation, pseudotumor cerebri, glaucoma and other fatal syndromes [31,32].…”

Section: Discussionmentioning

confidence: 99%

In Silico Study of Thymohydroquinone Interaction with blood–brain Barrier Disrupting Proteins

et al. 2020

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Aim: To evaluate the inhibitory interaction of thymohydroquinone against blood–brain barrier (BBB)-associated neuropsychiatric and neurodegenerative disorders. Materials & methods: An elaborated in silico study was designed to evaluate the interaction of thymohydroquinone with BBB-disrupting proteins and to highlight its pharmacokinetic and safety attributes. Results: Thymohydroquinone demonstrated stable interaction with BBB-disrupting protein active site with Ki (inhibition constant) ranges of (2.71 mM–736.15 μM), binding energy (-4.3 to 5.6 Kcal/mol), ligand efficiency (-0.36 to 0.42 Kcal/mol) and root mean square deviation value of (0.80–2.59 Å). Conclusion: Further pharmacokinetic analysis revealed that thymohydroquinone is BBB and central nervous system (CNS) permeant with high acute toxicity and could be a candidate drug for the treatment of these neurological conditions.

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“…Molecular docking studies have been undertaken to gain further insights into the possible interaction of molecules newly identified by protein‐ligand binding‐site prediction and to understand their mechanisms of action. Docking interactions for the p60TRP homo‐dimer protein were performed by the geometry‐based molecular docking algorithm PatchDock program as previously described43 and applied 44–46…”

Section: Methodsmentioning

confidence: 99%

3D Structure, Dimerization Modeling, and Lead Discovery by Ligand‐protein Interaction Analysis of p60 Transcription Regulator Protein (p60TRP)

Pramanik

Kutzner

Heese

2015

Molecular Informatics

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The p60 transcription regulator protein (p60TRP) is a basic helix-loop-helix (bHLH) domain-containing neuroprotective protein and a member of the G-protein-coupled receptor (GPCR)-associated sorting protein (GPRASP) family. In the present study, multiple theoretical physico-chemical methods (e.g. Modeller v.9.13, I-TASSER, PROCHECK and ClusPro v2.0 with PIPER) were applied to unveil the three-dimensional (3D) protein structure of the p60TRP homo-dimer protein and explore potential ligand-protein interactions. Our results suggest a Mg(2+) -containing 3D p60TRP dimer protein that potentially interacts with 5-(1-aziridinyl)-2,4-dinitrobenzamide (CB1954) and [2-(3-dodecylimidazolidin-1-yl)-1-phosphonoethyl] phosphonic acid (B73). The discovery of CB1954 and B73 may serve as a potential lead for further drug screening tests to normalize the p60TRP signaling pathway in neurodegenerative diseases. Interference with p60TRP signaling via CB1954/B73-related molecules might be a novel option for modifying neurodegenerative signaling pathways (e.g. RIN1, PP2A, RanBP5, CREB and SYNJ1) to treat various brain diseases.

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On the Inhibitory Affect of Some Dementia Drugs on DNA Polymerase β Activity

Cited by 4 publications

References 37 publications

Targeting DNA Polymerase ß for Therapeutic Intervention

Targeting DNA Polymerase ß for Therapeutic Intervention

In Silico Study of Thymohydroquinone Interaction with blood–brain Barrier Disrupting Proteins

3D Structure, Dimerization Modeling, and Lead Discovery by Ligand‐protein Interaction Analysis of p60 Transcription Regulator Protein (p60TRP)

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