Selection of potential natural compounds for poly-ADP-ribose polymerase (PARP) inhibition in glioblastoma therapy by in silico screening methods

Rajendran, Arunraj Tharamelveliyil; Rajesh, Gupta Dheeraj; Kumar, Pankaj; Dwivedi, Prarambh S. R.; Shastry, C. S.; Vadakkepushpakath, Anoop Narayanan

doi:10.1016/j.sjbs.2023.103698

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…In-silico and In-vitro evaluations have provided valuable insights into the activity of these compounds 10 . In our previous study, 50 phytocompounds were screened for their PARP inhibition potential in silico, and the most active compounds were shortlisted 11 . Among them, promising PARP inhibition was shown by naringin.…”

Section: Introductionmentioning

confidence: 99%

Uncovering Naringin’s Anticancer Mechanisms in Glioblastoma via Molecular Docking and Network Pharmacology Approaches

Rajendran,

Rajesh,

Ashtekar

et al. 2024

Preprint

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Naringin, a flavonoid, exhibits diverse therapeutic properties and has been proven to exert cytotoxic effects on cancer cells. Nevertheless, the precise mechanism of naringin maintaining its cytotoxic effect on glioblastoma (GBM) remains unknown. Thus, the current study aimed to establish a plausible cellular mechanism for Naringin's inhibition of GBM. We employed various system biology techniques to forecast the primary targets, including gene ontology and cluster analysis, KEGG enrichment pathway estimation, molecular docking, MD (molecular dynamic) simulation and MMPBSA analysis. Glioblastoma target sequences were obtained via DisGeNet and Therapeutic Target Prediction, aligned with naringin targets, and analyzed for gene enrichment and ontology. Gene enrichment analysis identified the top ten hub genes. Further, molecular docking was conducted on all identified targets. For molecular dynamics modelling, we selected the two complexes that exhibited the most docking affinity and the two most prominent genes of the hub identified through analysis of the enrichment of genes. The PARP1 and ALB1 signalling pathways were found to be the main regulated routes. Naringin exhibited the highest binding potential of -12.90 kcal/mol with PARP1 (4ZZZ), followed by ABL1 (2ABL), with naringin showing a -8.4 kcal/mol binding score, as determined by molecular docking. The molecular dynamic approach and MM-PBSA investigation revealed that the complex of Naringin, with 4ZZZ (PARP1) and, 2ABL(ABL1), demonstrated the highest stability. Analyses of the signalling pathway suggested that naringin may have anticancer effects against GBM by influencing the protein PARP and ALB1 levels. Since it was developed In-silico, this study will expand to validate the mechanism in wet labs.

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Section: Introductionmentioning

confidence: 99%

Uncovering Naringin’s Anticancer Mechanisms in Glioblastoma via Molecular Docking and Network Pharmacology Approaches

Rajendran,

Rajesh,

Ashtekar

et al. 2024

Preprint

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The recent advance and prospect of poly(ADP‐ribose) polymerase inhibitors for the treatment of cancer

Bai,

Yang,

Jia

et al. 2024

Medicinal Research Reviews

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Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long‐term medication‐induced drug resistance. Poly(ADP‐ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP‐DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first‐line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure–activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders.

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Uncovering naringin’s anticancer mechanisms in glioblastoma via molecular docking and network pharmacology approaches

Tharamelveliyil Rajendran,

Dheeraj Rajesh,

Ashtekar

et al. 2024

Sci Rep

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Naringin, a flavonoid, exhibits diverse therapeutic properties and has been proven to exert cytotoxic effects on cancer cells. Nevertheless, the precise mechanism of naringin maintaining its cytotoxic effect on glioblastoma (GBM) remains unknown. Thus, the current study aimed to establish a plausible cellular mechanism for Naringin’s inhibition of GBM. We employed various system biology techniques to forecast the primary targets, including gene ontology and cluster analysis, KEGG enrichment pathway estimation, molecular docking, MD (molecular dynamic) simulation and MMPBSA analysis. Glioblastoma target sequences were obtained via DisGeNet and Therapeutic Target Prediction, aligned with naringin targets, and analyzed for gene enrichment and ontology. Gene enrichment analysis identified the top ten hub genes. Further, molecular docking was conducted on all identified targets. For molecular dynamics modelling, we selected the two complexes that exhibited the most docking affinity and the two most prominent genes of the hub identified through analysis of the enrichment of genes. The PARP1 and ALB1 signalling pathways were found to be the main regulated routes. Naringin exhibited the highest binding potential of − 12.90 kcal/mol with PARP1 (4ZZZ), followed by ABL1 (2ABL), with naringin showing a − 8.4 kcal/mol binding score, as determined by molecular docking. The molecular dynamic approach and MM-PBSA investigation along with PCA study revealed that the complex of Naringin, with 4ZZZ (PARP1) and, 2ABL (ABL1), are highly stable compared to that of imatinib and talazoparib. Analyses of the signalling pathway suggested that naringin may have anticancer effects against GBM by influencing the protein PARP and ALB1 levels. Cytotoxicity assay was performed on two different glioblastoma cell lines C6 and U87MG cells. Naringin demonstrates a higher cytotoxic potency against U87MG human glioblastoma cells compared to C6 rat glioma cells.

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Selection of potential natural compounds for poly-ADP-ribose polymerase (PARP) inhibition in glioblastoma therapy by in silico screening methods

Cited by 3 publications

References 41 publications

Uncovering Naringin’s Anticancer Mechanisms in Glioblastoma via Molecular Docking and Network Pharmacology Approaches

Uncovering Naringin’s Anticancer Mechanisms in Glioblastoma via Molecular Docking and Network Pharmacology Approaches

The recent advance and prospect of poly(ADP‐ribose) polymerase inhibitors for the treatment of cancer

Uncovering naringin’s anticancer mechanisms in glioblastoma via molecular docking and network pharmacology approaches

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