Pharmacoinformatics approach for the screening of Kovidra (Bauhinia variegata) phytoconstituents against tumor suppressor protein in triple negative breast cancer

Abstract

Globally, 2.3 million women were diagnosed with breast cancer, with 6,85000 mortalities in year 2021; making it the world’s most prevalent cancer. This growing global burden necessitates a new treatment option, and plant-based medicines offers a promising alternative to conventional cancer treatment. In this work, screening of phytoconstituents of an indigenous therapeutic plant, Bauhinia variegata carried out for potential regulator of tumor suppressor protein p53. Here, an in-silico analysis was employed to develop more effective, pharmaceutically potent small drug-like compounds that target tumor suppressor protein p53. The methanol and aqueous powdered extracts of Bauhinia variegata were prepared and phytochemically evaluated along with antioxidant property evaluation. The LC₅₀ of methanol (325.33 µg/ml) and aqueous extract (361.15 µg/ml) showed their cytotoxic characteristics. Further, GCMS analysis of both the extracts reveals total 57 secondary metabolites. Among these, four lead compounds; compound 1, compound 2, compound 3 and compound 4 were found to have the highest binding ability (-8.15 to −5.40 kcal/mol) with p53. MD simulation and binding free energy validates these findings with highest binding free energy (-67.09 ± 4.87 kcal/mol) towards p53 by the lead phytocompound 2. Selected compounds exhibit excellent pharmacokinetic features and drug-like characteristics. The acute toxicity (LD₅₀) values of the lead phytocompounds ranges from 670 mg/kg to 3100 mg/kg, with toxicity classes of IV and V. As a result, these druggable phytochemicals could serve as potential lead applicants for triple negative breast cancer treatment. However, more in vitro and in vivo research is planned to produce future breast cancer medicine.

HIGHLIGHTS

• Screening of phytoconstituents of an indigenous therapeutic plant, Bauhinia variegata, for potential regulator of tumor suppressor protein p53.

• The LC₅₀ of methanol (325.33µg/ml) and aqueous extract (361.15µg/ml) showed their cytotoxic characteristics.

• GCMS analysis of both the extracts reveals total 57 secondary metabolites. Among these, four lead compounds were found to have the highest binding affinity (-8.153 to -5.401 kcal/mol) with tumor suppressor protein p53.

• MD simulation along with the Prime MM/GBSA binding free energy validates this discovery with highest binding free energy (-67.09 ± 4.87 kcal/mol) towards p53 by the lead compound 2.

• The acute toxicity (LD₅₀) values of the lead phytocompounds ranges from 670 mg/kg to 3100 mg/kg, with toxicity classes of IV and V.

• As a result, these druggable phytochemicals could serve as potential lead applicants for triple negative breast cancer treatment.

Communicated by Ramaswamy H. Sarma

Keywords:

• Triple negative breast cancer
• tumor suppressor protein p53
• Bauhinia variegata
• molecular docking
• dynamics simulations and MM/GBSA free energy calculations

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Acknowledgments

The authors would like to express their gratitude to the School of Pharmacy of MIT World Peace University for providing experimental facilities and equipment and Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune, for providing us an opportunity to perform research at the Bioinformatics Centre. The authors would also like to thank the DST-SERB, Government of India, New Delhi (File Number: YSS/2015/002035) for availing the Supercomputer resource for dynamics simulations. Mr. Kiran Bharat Lokhande wishes to express his gratitude to the ICMR (Indian Council of Medical Research), New Delhi, India, for the Senior Research Fellowship (Project ID: 2019-3458; file: ISRM/11(54)/2019). Senior Research Fellowship awarded to Mr. Ashish Shrivastava (Project ID: 2021‐14351; File No.: BMI/11(100)/2022) by the Indian Council of Medical Research, New Delhi is also acknowledged. The authors would also like to express their gratitude to Schrodinger and the crew for offering an Evaluation License.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

All docking structures are accessible upon demand from the corresponding author.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.