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Benzothiazole derivatives as p53-MDM2 inhibitors: in-silico design, ADMET predictions, molecular docking, MM-GBSA
Shridhar Deshpande N1, Shivakumar2, Udaya Kumar D2
1Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Nitte (Deemed to be University), Mangalore, Karnataka, India.
Abstract:
Breast cancer stands as the most prevalent malignancy among the female populace. One of the pivotal domains in the therapeutic landscape of breast cancer revolves around the precise targeting of the p53-MDM2 inhibitory pathway. The advent of p53-MDM2 inhibition in the context of developing treatments for breast cancer marks a significant stride. In the quest for enhancing the efficacy of p53-MDM2 inhibition against breast cancer, a new series of benzothiazole compounds (B1-B30) was designed through in-silico methodologies in the present work. Using Schrodinger Maestro, the compounds underwent molecular docking assessments against the p53-MDM2 target (PDB: 4OGT). Compared to reference compounds, B25 and B12 exhibited notably elevated glide scores. Extensive in-silico studies, including ADMET and toxicity evaluations, were performed to predict pharmacokinetics, drug likeness, and toxicity. All compounds adhered to Lipinski criteria, signifying favorable oral drug properties. The MM-GBSA analysis indicated consistent binding free energies. Molecular dynamics simulations for B25 over 200 ns assessed complex stability and interactions. In summary, these compounds exhibit potential for future cancer therapy medication development.
Insights
New benzothiazole compounds show promise for breast cancer treatment by targeting the p53-MDM2 pathway. Computational studies indicate favorable drug properties and potential for developing novel cancer therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- Breast cancer is the most common female malignancy.
- Targeting the p53-MDM2 inhibitory pathway is crucial for breast cancer treatment.
- Developing effective p53-MDM2 inhibitors is an active area of research.
Purpose of the Study:
- To design and evaluate novel benzothiazole compounds (B1-B30) as potential p53-MDM2 inhibitors for breast cancer therapy.
- To enhance the efficacy of p53-MDM2 inhibition against breast cancer using computational methods.
Main Methods:
- In-silico design and molecular docking of benzothiazole compounds against the p53-MDM2 target (PDB: 4OGT) using Schrodinger Maestro.
- In-silico ADMET and toxicity evaluations for pharmacokinetic and drug-likeness prediction.
- MM-GBSA analysis and 200 ns molecular dynamics simulations for B25 to assess binding energy and complex stability.
Main Results:
- Compounds B25 and B12 demonstrated superior glide scores compared to reference compounds.
- All designed compounds satisfied Lipinski's criteria, indicating good oral drug properties.
- MM-GBSA and molecular dynamics simulations confirmed the stability and favorable interactions of the compounds with the target.
Conclusions:
- The designed benzothiazole compounds exhibit significant potential as therapeutic agents for breast cancer.
- These compounds warrant further investigation for the development of novel cancer medications targeting the p53-MDM2 pathway.
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