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Comparisons of Prostate Cancer Inhibitors Abiraterone and TOK-001 Binding with CYP17A1 through Molecular Dynamics
Fei Xiao1, Maohua Yang1, Youjun Xu1
1School of Biology and Basic Medical Sciences, Medical College of Soochow University, 199 Ren ai Road, China-Singapore Industrial Park, Suzhou, JiangSu 215123, China.
Abstract:
Cytochrome P450 17A1 (CYP17A1) is associated in the steroid hormone biosynthesis in human. As cell proliferation of prostate cancer in response to androgen steroid, an inhibition of CYP17A1 becomes an alternative approach to inhibit biosynthesis of androgen and support treatment of prostate cancer. However, biology-driven inhibitor development of prostate cancer is poorly elucidated. The aims of this study are to address structural differences at atomic-level between CYP17A1 and inhibitors i.e., abiraterone and TOK-001, and further investigate the effect of point mutation of CYP17A1 on the active site stability and the local interactions that are hydrophobic interaction and hydrogen bonding throughout molecular dynamics (MD) simulation. After performing multiple comparisons among four different complexes across CYP17A1 and inhibitors, interestingly TOK-001 oriented toward the active pocket and formed larger volume with I-helix of CYP17A1 than abiraterone, whereas abiraterone showed tighter binding and more active site stability. Considering on the effect of hydrophobic interaction and hydrogen bonding between abiraterone and CYP17A1, the key residues of Phe114, Ile371, Val482, and Asn202 were identified. This contributes into tight binding interactions; however abiraterone is effectively weakened along with the global conformation mobility increased in A105L mutation. Surprisingly, overall conformation of the CYP17A1 remained stable when bound to TOK-001. This basic knowledge can guide future experiments on design of efficient inhibitors for CYP17A1, which provides theoretical basis of androgen-dependent disease therapy.
Insights
Inhibiting Cytochrome P450 17A1 (CYP17A1) targets prostate cancer by blocking androgen synthesis. Abiraterone offers stable binding, while TOK-001 maintains CYP17A1 conformation, guiding future drug design.
Area of Science:
- Biochemistry and Molecular Biology
- Medicinal Chemistry
- Computational Biology
Background:
- Cytochrome P450 17A1 (CYP17A1) is crucial for androgen biosynthesis, a key driver of prostate cancer cell proliferation.
- Inhibiting CYP17A1 is a therapeutic strategy for prostate cancer, but a detailed understanding of inhibitor interactions is lacking.
- The development of biology-driven CYP17A1 inhibitors requires atomic-level insights into enzyme-inhibitor dynamics.
Purpose of the Study:
- To elucidate atomic-level structural differences between CYP17A1 and inhibitors abiraterone and TOK-001.
- To investigate the impact of CYP17A1 point mutations on active site stability and local interactions (hydrophobic and hydrogen bonding).
- To provide a theoretical basis for designing novel, effective CYP17A1 inhibitors for androgen-dependent diseases.
Main Methods:
- Molecular dynamics (MD) simulations were employed to analyze four different CYP17A1-inhibitor complexes.
- Comparative analysis focused on active site orientation, pocket volume, binding interactions, and conformational stability.
- Identification of key residues involved in hydrophobic and hydrogen bonding interactions was performed.
Main Results:
- TOK-001 oriented within the active pocket, interacting with the I-helix and occupying a larger volume compared to abiraterone.
- Abiraterone demonstrated tighter binding and enhanced active site stability, with key residues Phe114, Ile371, Val482, and Asn202 identified.
- The A105L mutation weakened abiraterone's binding and increased global mobility, whereas TOK-001 binding maintained overall CYP17A1 conformational stability.
Conclusions:
- Abiraterone's tight binding is mediated by specific hydrophobic and hydrogen bonding interactions with key CYP17A1 residues.
- Mutations can significantly impact inhibitor efficacy, highlighting the need for mutation-aware drug design.
- TOK-001's ability to maintain CYP17A1 stability offers a promising avenue for developing next-generation prostate cancer therapeutics.
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