Targeting p53 misfolding conundrum by stabilizing agents and their analogs in breast cancer therapy: a comprehensive computational analysis

Burhan Ul Haq; Hina Qayoom; Shazia Sofi; Nusrat Jan; Aisha Shabir; Irshad Ahmad; Fuzail Ahmad; Abdullah Almilaibary; Manzoor A Mir

doi:10.3389/fphar.2023.1333447

Targeting p53 misfolding conundrum by stabilizing agents and their analogs in breast cancer therapy: a comprehensive computational analysis

Front Pharmacol. 2024 Jan 10:14:1333447. doi: 10.3389/fphar.2023.1333447. eCollection 2023.

Authors

Burhan Ul Haq¹, Hina Qayoom¹, Shazia Sofi¹, Nusrat Jan¹, Aisha Shabir¹, Irshad Ahmad², Fuzail Ahmad³, Abdullah Almilaibary⁴, Manzoor A Mir¹

Affiliations

¹ Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India.
² Department of Medical Rehabilitation Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia.
³ Respiratory Care Department, College of Applied Sciences, Almaarefa University, Diriya, Saudi Arabia.
⁴ Department of Family and Community Medicine, Faculty of Medicine, Al Baha University, Albaha, Saudi Arabia.

Abstract

Cancer continues to be a major global public health concern and one of the foremost causes of death. Delays in the diagnosis and cure may cause an increase in advanced stage disease and mortality. The most common cancer found in women currently is breast carcinoma. Breast carcinoma has surpassed lung carcinoma and currently represents the chief type of cancer diagnosed (2.3 million new cases, which amount to 11.7% of all cancer cases). In addition, by 2040, the incidence will increase by more than 46% as per the estimates of GLOBOCAN. Triple-negative breast cancer (TNBC) represents a highly aggressive and invasive subtype of breast cancer, characterized by rapid progression, short response time to the available treatment, and poor clinical results. Thus, it is very crucial to develop novel diagnostic tools and therapeutics with good efficacy. A majority of cancers display malfunction along the p53 pathway. Moreover, p53 not only loses its function but is also prone to misfolding and aggregation, leading to formation of amyloid aggregates as well. Research is being carried out to find ways to restore the normal action and expression of p53. Here, we have explored PhiKan-083 for its possible stabilizing effect on p53 in order to address the problem with its misfolding. Thus, examining the analogs of PhiKan-083 that have a role in p53 stability will help update our understanding of cancer progression and may expedite the progress of new anticancer treatments. We anticipate that the drug molecules and their analogs targeting p53 aggregation may be used in combination with other anticancer compounds to solve the problem with p53 aggregation. In this study, by employing ADMET analysis, the compounds were screened, and we further examined the chosen compounds with the help of molecular docking. By using databases like UALCAN, TIMER, GEPIA, and PredictProtein, we investigated TP53's expression pattern and prognostic relevance in various cancer settings.

Keywords: PhiKan-083; aggregation; breast cancer; molecular docking; mutation; p53 misfolding.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was funded by the Jammu and Kashmir Science Technology and Innovation Council Department of Science and Technology (JKDST), India, with grant no. JKST&IC/SRE/885-87 to MM. This study was also funded by the Deanship of Scientific Research, King Khalid University, Kingdom of Saudi Arabia, Project number-(RGP-2/286/44).