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Binding modes and conformational changes of FK506-binding protein 51 induced by inhibitor bindings: insight into
Jianzhong Chen1, Baohua Yin2, Laixue Pang1
1School of Science, Shandong Jiaotong University, Jinan, China.
Abstract:
The FK506-binding protein 51 (FKBP51) is a cochaperone that modulates the signal transduction of steroid hormone receptors and has been involved in prostate cancer, indicating that FKBP51 is an attractive target of drug design curing the related cancers. In this work, multiple short molecular dynamics (MSMD) simulations are combined with MM-GBSA method to investigate binding modes of inhibitors 3JP, 3JR and 3JQ to FKBP51. The results show that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP strengthen binding of 3JR and 3JQ to FKBP51. Principal component (PC) analysis performed on the equilibrated MSMD trajectories suggests that three inhibitor bindings produce significant effect on dynamics behavior and conformational changes of the loops L1, L2 and the domain β-L-α-L-β in FKBP51. The calculations of residue-based free energy decomposition not only recognize the hot interaction spot of inhibitors with FKBP51, but also display that the substitutions of diols (R)-19 and (S)-19 at the R position of 3JP play significant role in stronger binding of 3JR and 3JQ to FKBP51 than 3JP. This work is expected to provide theoretical hints and molecular mechanism for design of highly efficient inhibitors toward FKBP51.
Insights
FKBP51, a target for prostate cancer drugs, was studied using molecular dynamics. Inhibitors 3JR and 3JQ showed stronger binding than 3JP due to specific diol substitutions, offering insights for drug design.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- FKBP51 is a cochaperone influencing steroid hormone receptor signaling.
- FKBP51 involvement in prostate cancer makes it a key drug target.
Purpose of the Study:
- Investigate binding modes of inhibitors 3JP, 3JR, and 3JQ to FKBP51.
- Understand the molecular mechanisms behind inhibitor binding and efficacy.
Main Methods:
- Multiple short molecular dynamics (MSMD) simulations.
- Molecular Mechanics with Generalized Born Surface Area (MM-GBSA) calculations.
- Principal Component (PC) analysis and residue-based free energy decomposition.
Main Results:
- Substitutions of diols (R)-19 and (S)-19 at the R position of 3JP enhanced binding affinity in 3JR and 3JQ.
- Inhibitor binding significantly altered FKBP51 dynamics, particularly loops L1, L2, and the β-L-α-L-β domain.
- Identified key interaction sites and confirmed the role of diol substitutions in stronger binding.
Conclusions:
- The study provides a molecular understanding of FKBP51 inhibitor interactions.
- Results offer theoretical guidance for designing more potent FKBP51 inhibitors for cancer therapy.
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