Structure-based discovery of selective CYP17A1 inhibitors for Castration-resistant prostate cancer treatment
Damilola A Omoboyowa1, Toheeb A Balogun1, Oluwatosin A Saibu2
1Department of Biochemistry, Adekunle Ajasin University, Akungba-Akoko, Nigeria.
Abstract:
Prostate cancer (PCa) is the most common malignancy found in men and the second leading cause of cancer-related death worldwide. Castration-resistant PCa (CRPC) is defined by PCa cells that stop responding to hormone therapy. Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) plays a critical role in the biosynthesis of androgens in humans. Androgen signaling cascade is a principal survival pathway for PCa cells and androgen-deprivation therapy (ADT) remains the key treatment for patients marked with locally advanced and metastatic PCa cells. Available synthetic drugs have been reported for toxicity, drug resistance, and decreasing efficacy. Thus, the design of novel selective inhibitors of CYP17A1 lyase would help circumvent associated side effects and improve pharmacological activities. Therefore, we employed structural bioinformatics techniques via molecular docking; molecular mechanics generalized born surface area (MM-GBSA), molecular dynamics (MD) simulation, and pharmacokinetic study to identify putative CYP17A1 lyase inhibitors. The results of the computational investigation showed that the Prunus dulcis compounds exhibited higher binding energy than the clinically approved abiraterone acetate. The stability of the ligand with the highest binding affinity (quercetin-3-o-rutinoside) was observed during MD simulation for 10 ns. Quercetin-3-o-rutinoside was observed to be stable within the active site of CYP17A1Lyase throughout the simulation period. The result of the pharmacokinetic study revealed that these compounds are promising therapeutic agents. Collectively, this study proposed that bioactive compounds from P. dulcis may be potential selective inhibitors of CYP17A1Lyase in CRPC treatments.
Insights
Bioactive compounds from Prunus dulcis show promise as selective inhibitors for Castration-resistant Prostate Cancer (CRPC) treatment. These natural compounds exhibit higher binding affinity to CYP17A1 lyase than current drugs, suggesting potential for improved therapies.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in men, with Castration-resistant Prostate Cancer (CRPC) posing a significant therapeutic challenge.
- Androgen signaling is crucial for PCa cell survival, and while androgen-deprivation therapy (ADT) is standard, resistance and drug toxicity are common.
- Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a key enzyme in androgen biosynthesis, making it a target for CRPC treatment.
Purpose of the Study:
- To identify novel, selective inhibitors of CYP17A1 lyase using computational methods.
- To explore the potential of natural compounds from Prunus dulcis as therapeutic agents for CRPC.
- To overcome limitations of current synthetic drugs, including toxicity and resistance.
Main Methods:
- Molecular docking, MM-GBSA, and molecular dynamics (MD) simulations were employed to assess binding affinities and stability.
- Pharmacokinetic studies were conducted to evaluate the drug-like properties of identified compounds.
- In silico screening of compounds from Prunus dulcis against the CYP17A1 lyase enzyme.
Main Results:
- Compounds from Prunus dulcis demonstrated higher binding energy to CYP17A1 lyase compared to abiraterone acetate.
- Quercetin-3-o-rutinoside showed significant binding affinity and stability within the CYP17A1 lyase active site during 10 ns MD simulation.
- Pharmacokinetic analysis indicated that these natural compounds possess favorable properties for therapeutic development.
Conclusions:
- Bioactive compounds from Prunus dulcis are potential selective inhibitors of CYP17A1 lyase.
- Quercetin-3-o-rutinoside is a promising lead compound for developing new CRPC therapies.
- This study supports the exploration of natural products for overcoming resistance and toxicity in prostate cancer treatment.
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