Withanone binds to mortalin and abrogates mortalin-p53 complex: computational and experimental evidence.

Withanone binds to mortalin and abrogates mortalin-p53 complex: computational and experimental evidence.Mortalin binds to p53 tumor suppressor protein and sequesters it in the cytoplasm. This results in an inhibition of the transcriptional activation and control of centrosome duplication functions of p53, thus contributing to human carcinogenesis. Abrogation of mortalin-p53 interaction and reactivation of p53 function could be a valid proposition for cancer therapy. In the present study, we first investigated in silico the interaction of withanone, a withanolide with anticancer activity, with mortalin. We found that withanone could bind to mortalin in a region, earlier predicted critical for binding to p53. Cationic rhodacyanine dye, MKT-077 has also shown to bind the same region and kill cancer cells selectively. We report the molecular dynamic simulations revealing the thermodynamic and structural stability of the withanone-mortalin complexes. We also demonstrate the experimental evidence of abrogation of mortalin-p53 complex by withanone resulting in nuclear translocation and functional reactivation of p53 in human cancercells. The present study establishes a molecular interaction basis that could be used for screening and development of anticancer drugs with low toxicity to normal cells. Accurate knowledge of the 3D structure of mortalin would further enhance the potential of such analyses to understand the molecular basis of mortalin biology and mortalin based cancer therapy.

Identifications small molecules inhibitor of p53-mortalin complex for cancer drug using virtual screening.

Identifications small molecules inhibitor of p53-mortalin complex for cancer drug using virtual screening.
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 stopcancer 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.