Heat-shock proteins (HSPs), particularly HSP90, are critical molecular chaperones that maintain protein stability, especially in cancer cells. Elevated HSP90 levels in tumors aid in oncogenic protein stabilization. This study focuses on developing potent, selective HSP90 inhibitors to disrupt its chaperone function, targeting cancer cell survival. Using a de novo hybridization approach, we designed novel inhibitors by integrating structural fragments from a known HSP90-binding drug, leading to the creation of hybrid compounds C1, C2, and C3. A 300 ns molecular dynamics simulation of each system revealed that C1, C2, and C3 formed more stable complexes with HSP90 compared to the reference compound, MEY. RMSD, RMSF, Rg, SASA, and MM-PBSA metrics supported these findings. DCCM and FEL analyses confirmed that the inhibitors did not alter HSP90's initial configuration. Further DFT calculations with the B3LYP/6-311 + + (d,p) basis set were conducted to evaluate frontier molecular orbitals, MEP surfaces, ELF, LOL maps, TDOS and PDOS. The results indicated that C1, C2, and C3 formed more stable complexes with HSP90 compared to the reference compound MEY. These findings affirm the potential of C1, C2, and C3 as new anti-cancer therapies. Our approach demonstrates a promising strategy for developing selective HSP90 inhibitors that maintain the protein's functional integrity while disrupting its oncogenic role, paving the way for further preclinical evaluation of these novel compounds.

METHODS:

Maestro 11.8, Discovery Studio Visualizer, Gromacs-2023, Gaussian 16, and online platforms like SwissADME and ProTox-II were utilized. Fragments generated from eight known HSP90-binding drugs were subjected to SP-docking, leading to 170 fragments. The highest-scoring fragments were merged using the breed panel to create new HSP90 inhibitors. XP-docking and ADMET analyses identified C1, C2, and C3 as the most promising candidates. These compounds were selected for a 300 ns dynamic simulation and subsequent DFT calculations.

2024-11-25·Journal of Chemical Information and Modeling

Mixture-of-Experts Based Dissociation Kinetic Model for De Novo Design of HSP90 Inhibitors with Prolonged Residence Time

Article

作者: Zhao, Yujing ; Liu, Qilei ; Zhang, Li ; Sun, Liang ; Zhang, Lei ; Du, Jian ; Meng, Qingwei ; Wang, Heshuang

The dissociation rate constant (k_off) significantly impacts the drug potency and dosing frequency. This work proposes a powerful optimization-based framework for de novo drug design guided by k_off. First, a comprehensive database containing 2,773 unique k_off values is created. Based on the database, a novel generic dissociation kinetic model is developed with a mixture-of-experts architecture, enabling high-throughput predictions of k_off with high accuracy. The developed model is then integrated with an optimization-based mathematical programming approach to design drug candidates with low k_off. Finally, the τ-RAMD method is utilized to rigorously verify the designed potential drug candidates. In a case study, the framework successfully identified numerous new potential HSP90 inhibitor candidates, achieving a maximum 45.7% improvement in residence time (τ = 1/k_off) compared to that of a known exceptional HSP90 inhibitor. These findings demonstrate the feasibility and effectiveness of the kinetics-guided optimization-based de novo drug design framework in designing drug candidates with prolonged τ.

2023-08-01·European review for medical and pharmacological sciences

BIIB021, an orally available and small-molecule inhibitor of HSP90, activates intrinsic apoptotic pathway in human cervical adenocarcinoma cell line (HeLa).

Article

作者: Güven, C M ; Özgür, A

OBJECTIVE:

Heat shock protein 90 (HSP90) is a highly conserved ATP-dependent chaperone protein that plays a vital role in tumorigenesis. This study aims to investigate the apoptosis inducer role of BIIB021 (orally available HSP90 inhibitors) compound via inhibition of HSP90 activity in the human cervical cancer cell line (HeLa).

PATIENTS AND METHODS:

The anticancer potential of BIIB021 was determined by XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)] cell proliferation assay against the human cervical cancer cell line (HeLa). ATPase and luciferase aggregation assays were carried out to detect the HSP90 inhibitor potential of BIIB021. To determine the antiproliferative mechanism of the BIIB021, the expression level of the pro-apoptotic and antiapoptotic markers was determined by reverse transcription polymerase chain reaction (RT-PCR) and ELISA experiments.

RESULTS:

BIIB021 exhibited a cytotoxic effect on HeLa cell proliferation and the inhibitory concentration (IC)50 dose of BIIB021 was found to be 14.79 nM at 48 h. BIIB021 decreased the ATP hydrolysis rate of HSP90 and blocked the refolding of the desaturated luciferase in the presence of ATP. To understand the antiproliferative mechanism of the BIIB021 in HeLa cells, the mRNA and protein expression levels of the apoptotic markers [BCL-2 associated X (BAX), B-cell lymphoma 2 (BCL-2), cytochrome-c (CYT-c), and caspase-3 (CAS-3)] were determined by RT-PCR and ELISA experiments. The results obtained indicated that BIIB021 decreased BCL-2 levels and increased BAX, CYT-c, and CAS-3 levels in human cervical cancer cells.

CONCLUSIONS:

These results confirmed that BIIB021 inhibited the chaperone activity of HSP90, resulting in anti-proliferating effects in cervical cancer cells via the induction of the intrinsic apoptotic pathways.

100 项与 HSP90 inhibitors(JMackem) 相关的药物交易

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