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Identifications small molecules inhibitor of p53-mortalin complex for cancer drug using virtual screening
Didik H Utomo1, Nashi Widodo, M Rifa'i
1Biology Department, Faculty of Sciences, Brawijaya University, Malang, Indonesia.
Abstract:
Mortalin was over expressed in tumor cells and bind to p53 protein. This interaction was suggested to promote sequestration of p53 in the cytoplasm, thereby inhibiting its nuclear activity. The p53 is a tumor suppressor that is essential for the prevention of cancer development and loss of p53 function is one of the early events in immortalization of human cells. Therefore, abrogation p53-mortalin interaction using small molecule is guaranteed stop cancer cell grow. However study interaction of p53-mortalin, and its inhibition using small molecule is still challenging because specific site of mortalin that bind to p53, vice versa, is still debatable. This study has aims to analyze the p53-binding site of mortalin using molecular docking and to screen drug-like compounds that have potential as inhibitors of p53-mortalin interaction using virtual screening. The result showed that the lowest energy binding of p53-mortalin complex is -31.89 kcal/mol, and p53 protein bind to substrate binding domain of mortalin (THR433; VAL435; LEU436; LEU437; PRO442; ILE558; LYS555). Furthermore, the p53-binding domain of mortalin was used as receptor to screen 9000 drug-like compounds from ZINC database using molecular docking program Auto Dock Vina in PyRx 0.8 (Virtual Screening Tools). Here, we have identified three drug-like compounds that are ZINC01019934, ZINC00624418 and ZINC00664532 adequate to interrupt stability of p53-mortalin complex that warrant for anticancer agent.
Insights
Researchers identified key binding sites between mortalin and the tumor suppressor p53. They screened compounds to disrupt this interaction, finding three potential anticancer agents that inhibit mortalin-p53 complex stability.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Mortalin overexpression in tumor cells binds to p53, sequestering it in the cytoplasm and inhibiting its tumor-suppressive nuclear activity.
- Loss of p53 function is an early event in human cell immortalization, making its interaction with mortalin a target for cancer therapy.
- Understanding the specific binding sites of mortalin and p53 is crucial for developing small molecules to disrupt their interaction.
Purpose of the Study:
- To identify the p53-binding site on mortalin using molecular docking.
- To screen for drug-like compounds that can inhibit the p53-mortalin interaction via virtual screening.
Main Methods:
- Molecular docking was employed to analyze the p53-mortalin complex and determine binding sites.
- Virtual screening of 9000 drug-like compounds from the ZINC database was performed using Auto Dock Vina in PyRx 0.8.
- The substrate binding domain of mortalin, identified through docking, served as the receptor for virtual screening.
Main Results:
- The lowest energy binding of the p53-mortalin complex was determined to be -31.89 kcal/mol.
- p53 protein was found to bind to the substrate binding domain of mortalin, specifically at residues THR433, VAL435, LEU436, LEU437, PRO442, ILE558, and LYS555.
- Three drug-like compounds (ZINC01019934, ZINC00624418, and ZINC00664532) were identified as potential inhibitors capable of disrupting the p53-mortalin complex stability.
Conclusions:
- The study successfully mapped the p53-binding site on mortalin.
- Identified compounds show promise as novel anticancer agents by interfering with the mortalin-p53 interaction.
- These findings provide a foundation for developing targeted therapies against cancers driven by mortalin-p53 dysregulation.
