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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Molecular dynamics-based identification of novel natural mortalin-p53 abrogators as anticancer agents
Neha Nagpal1, Sukriti Goyal1, Jaspreet Kaur Dhanjal1
1a School of Biotechnology, Jawaharlal Nehru University , New Delhi , India and.
Introduction:
Cancer is one of the leading causes of mortality worldwide that requires attention in terms of extensive study and research. Eradication of mortalin-p53 interaction that leads to the inhibition of transcriptional activation or blocking of p53 from functioning as a suppressor and induction of nuclear translocation of p53 can prove to be one of the useful approaches for cancer management.
Results:
In this study, we used structure-based approach to target the p53-binding domain of mortalin in order to prevent mortalin-p53 complex formation. We screened compounds from ZINC database against the modeled mortalin protein using Glide virtual screening. The top two compounds, DTOM (ZINC 28639308) and TTOM (ZINC 38143676) with Glide score of -12.27 and -12.16, respectively, were identified with the potential to abrogate mortalin-p53 interaction. Finally, molecular dynamics simulations were used to analyze the dynamic stability of the ligand-bound complex and it was observed that residues Tyr196, Asn198, Val264 and Thr267 were involved in intermolecular interactions in both the simulated ligand-bound complexes, and thus, these residues may have a paramount role in stabilizing the binding of the ligands with the protein.
Conclusion:
These detailed insights can further facilitate the development of potent inhibitors against mortalin-p53 complex.
Insights
Researchers identified two compounds, DTOM and TTOM, that can disrupt the mortalin-p53 interaction, a key target for cancer management. These findings may lead to new cancer therapies by inhibiting tumor suppressor protein p53 dysfunction.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Cancer remains a leading global cause of mortality, necessitating novel therapeutic strategies.
- The interaction between mortalin and p53 plays a critical role in cancer progression by inhibiting p53's tumor-suppressive functions.
Purpose of the Study:
- To identify small molecules that can disrupt the mortalin-p53 interaction.
- To explore a structure-based approach targeting the p53-binding domain of mortalin.
Main Methods:
- Utilized Glide virtual screening of the ZINC database against a modeled mortalin protein.
- Employed molecular dynamics simulations to analyze the stability of ligand-protein complexes.
Main Results:
- Identified two potential inhibitors, DTOM (ZINC 28639308) and TTOM (ZINC 38143676), with high Glide scores.
- Molecular dynamics simulations revealed key residues (Tyr196, Asn198, Val264, Thr267) involved in stabilizing ligand binding.
Conclusions:
- The identified compounds show potential for abrogating mortalin-p53 interaction.
- These insights can guide the development of novel inhibitors targeting the mortalin-p53 complex for cancer therapy.
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