In-silico designing of a potent ligand molecule against PTEN (Phosphatase and tensin homolog) implicated in Breast Cancer

Mukta Raghav; Varruchi Sharma; Shagun Gupta; Ankur Kaushal; Amit Vashishth; Hardeep Singh Tuli; Kuldeep Dhama; Anil Sharma

doi:10.18006/2022.10(4).840.845

Authors

Mukta Raghav Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India https://orcid.org/0000-0001-8789-4382
Varruchi Sharma Department of Biotechnology & Bioinformatics, Sri Guru Gobind Singh College Sector 26, Chandigarh. https://orcid.org/0000-0002-0465-8075
Shagun Gupta Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India https://orcid.org/0000-0002-1981-8801
Ankur Kaushal Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India https://orcid.org/0000-0002-5922-4047
Amit Vashishth Department of Science and Humanities, SRM Institute of Science & Technology (Deemed to be University) Ghaziabad 201204 (UP). https://orcid.org/0000-0003-0803-1891
Hardeep Singh Tuli Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India https://orcid.org/0000-0003-1155-0094
Kuldeep Dhama Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, UP, India. https://orcid.org/0000-0001-7469-4752
Anil Sharma Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, Haryana, 133207, India https://orcid.org/0000-0002-9768-1644

DOI:

https://doi.org/10.18006/2022.10(4).840.845

Keywords:

Breast cancer, PTEN, CADD, Inhibitor, Mutation, Therapy, Lead molecule

Abstract

Breast cancer has been attributed to be the second most common malignancy in females worldwide after skin cancer associated with a significantly high mortality rate. Tumor suppressor genes have an indispensable role in maintaining genomic integrity as well as cell cycle regulation. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is one of the most frequently mutated human tumor suppressor genes, implicated in cell growth, survival, and suppressing tumor formation. As the tumor progresses to more advanced stages, genetic alterations tend to increase one such alteration is the mutation of the PTEN gene which is linked to programmed cell death and maintenance of cell cycle regulation. There is a syndrome known as Cowden syndrome associated with a high risk of breast cancer which is a result of an outcome of germline mutations in the PTEN gene. Loss of PTEN activity, either at the protein or genomic level, has been related to many primary and metastatic malignancies including breast cancer. This study focuses on developing a potential bioavailable ligand inhibitory molecule for PTEN, using a computer-aided drug design approach (CADD). A library of developed ligands consisting of 50 potential molecules was screened to find a potential candidate to be used for second generation drug development. Among them, LIG28 was adjudged as the most effective and potential PTEN inhibitor given its maximum binding affinity of ΔG -5.96Kcal/mole with a lower RMSD value. Carmer’s Rule of toxicity further revealed the compatibility and non-toxicity of the molecule. These observations underscore the importance of PTEN as a target in the development of tumorigenesis and the prognosis of breast cancer.

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