In Silico Assessment and Molecular Docking Studies of Some Phyto-Triterpenoid for Potential Disruption of Mortalin-p53 Interaction

Pham, Minh Quan; Thi, Thuy Huong Le; Pham, Quoc Long; Lệ, Lê Thị; Dao, Huy Toan; Le, Dang Thi Thanh; Pham, Dung Thuy Nguyen; Thi, Hai Ha Pham

doi:10.3390/pr9111983

Cited by 3 publications

(1 citation statement)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Different methods of virtual screening that could be applied in the discovery and development of protein-protein interaction inhibitors were excellently reviewed elsewhere ( Macalino et al, 2018 ; Wu et al, 2019 ). Virtual screenings were previously applied in the successful identification of protein-protein interaction inhibitors, for instance, TCF/β-catenin ( Tian et al, 2012 ), 14-3-3/aminopeptidase N ( Thiel et al, 2013 ), Ubc13/Uevl ( Scheper et al, 2010 ), mortalin/p53 ( Pham et al, 2021 ; Utomo et al, 2012 ; Nagpal et al, 2017 ; Hartati and Djauhari, 2020 ), and MDM2/p53 ( Lawrence et al, 2009 ).…”

Section: Challenges and Strategies For Targeting Protein-protein Inte...mentioning

confidence: 99%

Abrogating the Interaction Between p53 and Mortalin (Grp75/HSPA9/mtHsp70) for Cancer Therapy: The Story so far

Elwakeel

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

p53 is a transcription factor that activates the expression of a set of genes that serve as a critical barrier to oncogenesis. Inactivation of p53 is the most common characteristic in sporadic human cancers. Mortalin is a differentially sub-cellularly localized member of the heat shock protein 70 family of chaperones that has essential mitochondrial and extra-mitochondrial functions. Elevated mortalin levels in multiple cancerous tissues and tumor-derived cell lines emphasized its key role in oncogenesis. One of mortalin’s major oncogenic roles is the inactivation of p53. Mortalin binds to p53 sequestering it in the cytoplasm. Hence, p53 cannot freely shuttle to the nucleus to perform its tumor suppressor functions as a transcription factor. This protein-protein interaction was reported to be cancer-specific, hence, a selective druggable target for a rationalistic cancer therapeutic strategy. In this review article, the chronological identification of mortalin-p53 interactions is summarized, the challenges and general strategies for targeting protein-protein interactions are briefly discussed, and information about compounds that have been reported to abrogate mortalin-p53 interaction is provided. Finally, the reasons why the disruption of this druggable interaction has not yet been applied clinically are discussed.

show abstract

Section: Challenges and Strategies For Targeting Protein-protein Inte...mentioning

confidence: 99%

Abrogating the Interaction Between p53 and Mortalin (Grp75/HSPA9/mtHsp70) for Cancer Therapy: The Story so far

Elwakeel

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

Bio-computational modeling, POM analysis and molecular dynamic simulation for novel synthetic quinolone and benzo[d][1,3]oxazine candidates as antimicrobial inhibitors

Elsayed,

Abdu,

Marzouk

et al. 2024

Sci Rep

View full text Add to dashboard Cite

The current study offers a metal-free, direct, and successful synthesis technique for a new series of quinolinone and benzo[d][1,3]oxazine, along with an assessment of their biological activities. Heteroannulation of anthranilic acid with carbonyl-containing chemicals (aroyl pyruvate, ethyl acetoacetatete, maleic anhydride, and ethyl cyanoacetate) resulted in the desired quinolones and benzo[d][1,3]oxazines. This technique introduces a number of fundamental breakthroughs in organic synthesis, including metal-free catalysts, smart reaction conditions with column purification, and a wide functional scope. Furthermore, the structure of the newly synthesized chemical series was investigated and validated using spectroscopic techniques. The synthesized series were evaluated for antibacterial (against gram-positive and gram-negative bacterial strains) and antifungal activity. The quinolone and benzo[d][1,3]oxazine candidates had remarkable antibacterial action. Furthermore, molecular docking investigations corroborated the biological studies using the Molecular Operating Environment and Petro Osiris Molinspiration (POM) experiments, which confirmed the activity of compounds 8 , 15 , and 17 . Our studies on the cytotoxic activity of various chemicals have demonstrated that these compounds exhibit minimal toxicity. Specifically, when comparing the cytotoxic effects on human lung fibroblast (WI38) cells to those of Doxorubicin , a well-known chemotherapy agent, compounds 8 , 15 , and 17 showed weak cytotoxic effects on the normal WI38 cells. This indicates that these compounds may possess some level of selectivity and reduced toxicity towards normal cells, suggesting potential for further exploration as antibacterial agents with a safer profile for normal cells. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-73972-x.

show abstract

Crinum jagus: antiproliferative studies of extracts on HepG2 cell line and in silico assessment of phytoconstituents as potential inhibitors of p53–mortalin interaction

et al. 2023

View full text Add to dashboard Cite

Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide and has a poor prognosis in black Africans. Traditional herbal practitioners in southwestern Nigeria use Crinum jagus (J. Thompson) Dandy for cancer treatment. This study screens methanol and ethyl acetate extracts of C. jagus leaves for activity against hepatocellular carcinoma (HepG2) cell line using the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The antiproliferative properties of the extracts were assessed by comparing their IC50 values with that of the standard drug, cisplatin. The GC–MS technique was used to identify the phytoconstituents in the extracts. The drug-likeness of each identified phytoconstituents in the extracts was determined by following Lipinski’s rule of five. In addition, phytoconstituents having drug-like properties were screened as potential inhibitors of the p53–mortalin interaction by docking them against the mortalin residues 3N8E and 4KBO using Swissdock. Results For the antiproliferative study, the IC50 values obtained for cisplatin, methanol, and ethyl acetate extracts of leaves were 5 µg/mL, 5 µg/mL, and 70 µg/mL, respectively, indicating that the methanol extract and cisplatin possess comparable antiproliferative properties. Hexadecanoic acid, hexadecanoic acid methyl ester, tangeretin, galanthamine, and crinamine, which were part of the constituents identified in the leaves, possess drug-like properties and are known to show cytotoxic properties against several cancer cell lines. On docking with mortalin residue 3N8E, hexadecanoic acid and hexadecanoic acid methyl ester had comparable binding energy (− 8.21 kcal mol−1) with withaferin A and withanone (8.29 kcal mol−1 and 8.14 kcal mol−1). Hexadecanoic acid, hexadecanoic acid methyl ester, and galanthamine had binding energy of − 7.66, − 7.45, and − 7.47 kcal mol−1, respectively, with mortalin residue, 4KBO, comparable to values of − 7.68 and − 7.59 kcal mol−1 obtained for withaferin A and withanone, respectively. Conclusion The methanol extract of C. jagus leaves demonstrated remarkable antiproliferative activities against HepG2, justifying its use in traditional medicine for cancer treatment. The ethyl acetate and methanol extracts contain drug-like compounds with known cytotoxic properties against several cancer cell lines. Some of these compounds (hexadecanoic acid, hexadecanoic acid methyl ester, tangeretin, and galanthamine) are inhibitors of the p53–mortalin interaction. Graphical Abstract

show abstract

In Silico Assessment and Molecular Docking Studies of Some Phyto-Triterpenoid for Potential Disruption of Mortalin-p53 Interaction

Cited by 3 publications

References 29 publications

Abrogating the Interaction Between p53 and Mortalin (Grp75/HSPA9/mtHsp70) for Cancer Therapy: The Story so far

Abrogating the Interaction Between p53 and Mortalin (Grp75/HSPA9/mtHsp70) for Cancer Therapy: The Story so far

Bio-computational modeling, POM analysis and molecular dynamic simulation for novel synthetic quinolone and benzo[d][1,3]oxazine candidates as antimicrobial inhibitors

Crinum jagus: antiproliferative studies of extracts on HepG2 cell line and in silico assessment of phytoconstituents as potential inhibitors of p53–mortalin interaction

Contact Info

Product

Resources

About