Molecular docking and NMR binding studies to identify novel inhibitors of human phosphomevalonate kinase

Boonsri, Pornthip; Neumann, Terrence S.; Olson, Andrew L.; Cai, Shuqun; Herdendorf, Timothy J.; Miziorko, Henry M.; Hannongbua, Supa; Sem, Daniel S.

doi:10.1016/j.bbrc.2012.10.130

Cited by 6 publications

(6 citation statements)

References 31 publications

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“…Differently from MVK, this enzyme does not present feedback inhibition from its products [ 6 ]. However, various compounds were recently found to be inhibitors for this enzyme, suggesting novel mechanisms to inhibit the mevalonate pathway [ 7 ] and more interestingly, phosphomevalonate kinase appears also to be regulated by cholesterol shortage, as for mevalonate kinase and HMGR [ 8 ]. Indeed, cholesterol shortage induces increases in all the three first enzymes of the mevalonate pathway, thus guaranteeing a continued supply of this key membrane component ( Figure 1 a, 4).…”

Section: Mevalonate Pathwaymentioning

confidence: 99%

Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link

Tricarico

Crovella

Celsi

2015

IJMS

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The mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes. Deregulation of this pathway is also correlated with diminished protein prenylation, an important post-translational modification necessary to localize certain proteins, such as small GTPases, to membranes. Mevalonate pathway blockade has been linked to mitochondrial dysfunction: especially involving lower mitochondrial membrane potential and increased release of pro-apoptotic factors in cytosol. Furthermore a severe reduction of protein prenylation has also been associated with defective autophagy, possibly causing inflammasome activation and subsequent cell death. So, it is tempting to hypothesize a mechanism in which defective autophagy fails to remove damaged mitochondria, resulting in increased cell death. This mechanism could play a significant role in Mevalonate Kinase Deficiency, an autoinflammatory disease characterized by a defect in Mevalonate Kinase, a key enzyme of the mevalonate pathway. Patients carrying mutations in the MVK gene, encoding this enzyme, show increased inflammation and lower protein prenylation levels. This review aims at analysing the correlation between mevalonate pathway defects, mitochondrial dysfunction and defective autophagy, as well as inflammation, using Mevalonate Kinase Deficiency as a model to clarify the current pathogenetic hypothesis as the basis of the disease.

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Section: Mevalonate Pathwaymentioning

confidence: 99%

Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link

Tricarico

Crovella

Celsi

2015

IJMS

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“…An in-house physical collection of 10, 573 chemical ligands in the Center for Structure-based Drug Design and Development (CSD3) was used [38], [26], [25]. The library contains drug-like molecules, selected on the basis of their predicted binding to dehydrogenases and kinases, a general compliance with the Lipinski Rule of Five, and other drug-like filters.…”

Section: Methodsmentioning

confidence: 99%

“…The ligands were converted into a ready-to-dock format using Autodock tools [39]. The applicability and performance on of this chemical library has been demonstrated in our previous docking studies [26], [25]. The steps for the preparation of the files for the experiment are provided in supplemental file 1.…”

Section: Methodsmentioning

confidence: 99%

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A Novel Scoring Based Distributed Protein Docking Application to Improve Enrichment

Pradeep

Struble

Neumann

et al. 2015

IEEE/ACM Trans. Comput. Biol. and Bioinf.

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Molecular docking is a computational technique which predicts the binding energy and the preferred binding mode of a ligand to a protein target. Virtual screening is a tool which uses docking to investigate large chemical libraries to identify ligands that bind favorably to a protein target. We have developed a novel scoring based distributed protein docking application to improve enrichment in virtual screening. The application addresses the issue of time and cost of screening in contrast to conventional systematic parallel virtual screening methods in two ways. Firstly, it automates the process of creating and launching multiple independent dockings on a high performance computing cluster. Secondly, it uses a Nȧive Bayes scoring function to calculate binding energy of un-docked ligands to identify and preferentially dock (Autodock predicted) better binders. The application was tested on four proteins using a library of 10,573 ligands. In all the experiments, (i). 200 of the 1000 best binders are identified after docking only ∼ 14% of the chemical library, (ii). 9 or 10 best-binders are identified after docking only ∼ 19% of the chemical library, and (iii). no significant enrichment is observed after docking ∼ 70% of the chemical library. The results show significant increase in enrichment of potential drug leads in early rounds of virtual screening.

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“…Phosphomevalonate kinase, one of the mevalonate pathway kinases, catalyzes the phosphorylation step in isoprenoid/sterol biosynthesis and provides various biomolecules, including cholesterol, dolichol, ubiquinone, bile acids, prenylated proteins, vitamin, and heme A, which are required for normal cell growth and signaling. 21 , 22 Although PMVK is ubiquitously expressed in various cancers, including bladder, lung, colorectal, and breast, the detailed roles of PMVK in cancers remain unclear. In particular, the potential role of PMVK as a radiosensitizer has not been previously studied in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Targeting phosphomevalonate kinase enhances radiosensitivity via ubiquitination of the replication protein A1 in lung cancer cells

Park

Kwon

et al. 2023

Cancer Science

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Radiotherapy (RT) plays an important role in localized lung cancer treatments. Although RT locally targets and controls malignant lesions, RT resistance prevents RT from being an effective treatment for lung cancer. In this study, we identified phosphomevalonate kinase (PMVK) as a novel radiosensitizing target and explored its underlying mechanism. We found that cell viability and survival fraction after RT were significantly decreased by PMVK knockdown in lung cancer cell lines. RT increased apoptosis, DNA damage, and G2/M phase arrest after PMVK knockdown. Also, after PMVK knockdown, radiosensitivity was increased by inhibiting the DNA repair pathway, homologous recombination, via downregulation of replication protein A1 (RPA1). RPA1 downregulation was induced through the ubiquitin–proteasome system. Moreover, a stable shRNA PMVK mouse xenograft model verified the radiosensitizing effects of PMVK in vivo. Furthermore, PMVK expression was increased in lung cancer tissues and significantly correlated with patient survival and recurrence. Our results demonstrate that PMVK knockdown enhances radiosensitivity through an impaired HR repair pathway by RPA1 ubiquitination in lung cancer, suggesting that PMVK knockdown may offer an effective therapeutic strategy to improve the therapeutic efficacy of RT.

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Molecular docking and NMR binding studies to identify novel inhibitors of human phosphomevalonate kinase

Cited by 6 publications

References 31 publications

Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link

Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link

A Novel Scoring Based Distributed Protein Docking Application to Improve Enrichment

Targeting phosphomevalonate kinase enhances radiosensitivity via ubiquitination of the replication protein A1 in lung cancer cells

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