scholarly journals Complex Crystal Structure Determination and in vitro Anti–non–small Cell Lung Cancer Activity of Hsp90N Inhibitor SNX-2112

2021 ◽  
Vol 9 ◽  
Author(s):  
Dong Zhao ◽  
Yi-Ming Xu ◽  
Lu-Qi Cao ◽  
Feng Yu ◽  
Huan Zhou ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Molecular Interaction ◽  
Small Cell ◽  
Lead Compound ◽  
Small Cell Lung ◽  
Complex Crystal Structure ◽  
Complex Crystal

SNX-2112, as a promising anticancer lead compound targeting heat shock protein 90 (Hsp90), absence of complex crystal structure of Hsp90N-SNX-2112 hindered further structural optimization and understanding on molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90N-SNX-2112 was successfully determined by X-ray diffraction, resolution limit, 2.14 Å, PDB ID 6LTK, and their molecular interaction was analyzed in detail, which suggested that SNX-2112 was well accommodated in the ATP-binding pocket to disable molecular chaperone activity of Hsp90, therefore exhibiting favorable inhibiting activity on three non–small cell lung cancer (NSCLC) cell lines (IC50, 0.50 ± 0.01 μM for A549, 1.14 ± 1.11 μM for H1299, 2.36 ± 0.82 μM for H1975) by inhibited proliferation, induced cell cycle arrest, and aggravated cell apoptosis. SNX-2112 exhibited high affinity and beneficial thermodynamic changes during the binding process with its target Hsp90N confirmed by thermal shift assay (TSA, ΔTm, and −9.51 ± 1.00°C) and isothermal titration calorimetry (Kd, 14.10 ± 1.60 nM). Based on the complex crystal structure and molecular interaction analysis, 32 novel SNX-2112 derivatives were designed, and 25 new ones displayed increased binding force with the target Hsp90N verified by molecular docking evaluation. The results would provide new references and guides for anti-NSCLC new drug development based on the lead compound SNX-2112.

Complex crystal structure determination and anti-non-small-cell lung cancer activity of the Hsp90N inhibitor Debio0932

2021 ◽  
Vol 77 (1) ◽  
pp. 86-97
Author(s):  
Wei Qin ◽  
Feng Yu ◽  
Huan Zhou ◽  
Ping Li ◽  
Fang Zhou ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Molecular Chaperone ◽  
Molecular Interaction ◽  
Interaction Mechanism ◽  
Binding Pocket ◽  
Small Cell ◽  
Lead Compound ◽  
Small Cell Lung

Debio0932 is a promising lead compound in phase I clinical trials targeting the N-terminal ATP-binding pocket of the molecular chaperone heat-shock protein 90 (Hsp90N). The absence of a crystal structure of the Hsp90N–Debio0932 complex, however, has impeded further structural optimization of Debio0932 and understanding of the molecular-interaction mechanism. Here, a high-resolution crystal structure of the Hsp90N–Debio0932 complex was successfully determined (resolution limit 2.20 Å; PDB entry 6lr9) by X-ray diffraction and the molecular-interaction mechanism was analysed in detail, which suggested that Debio0932 suppresses cancer cells by accommodating itself in the ATP-binding pocket of Hsp90N, disabling its molecular-chaperone capability. The results of a thermal shift assay (ΔT m = 8.83 ± 0.90°C) and isothermal titration calorimetry (K d = 15.50 ± 1.30 nM) indicated strong binding and favourable thermodynamic changes in the binding of Hsp90N and Debio0932. Based on the crystal structure of the complex and on molecular-interaction analysis, 30 new Debio0932 derivatives were designed and nine new derivatives exhibited increased binding to Hsp90N, as determined by molecular-docking evaluation. Additionally, Debio0932 suppressed cell proliferation (IC50 values of 3.26 ± 2.82 µM for A549, 20.33 ± 5.39 µM for H1299 and 3.16 ± 1.04 µM for H1975), induced cell-cycle arrest and promoted apoptosis in three non-small-cell lung cancer (NSCLC) cell lines. These results provide novel perspectives and guidance for the development of new anti-NSCLC drugs based on the lead compound Debio0932.

scholarly journals Discovery of Eriodictyol as Putative Exportin-1 Inhibitor for Non-small Cell Lung Cancer Therapy

2020 ◽  
Author(s):  
Temidayo Olamide Adigun ◽  
Ireoluwa Yinka Joel ◽  
Olukayode Olusola Bankole ◽  
George Oche Ambrose ◽  
Oluwatobi Ayodeji Medayedupin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Binding Free Energy ◽  
Small Cell ◽  
Lead Compound ◽  
Small Cell Lung ◽  
Juglans Mandshurica ◽  
Synthetic Accessibility ◽  
Lung Cancer Therapy

Exportin-1, the ubiquitous nuclear protein transporter, is widely confirmed as an active chemotherapeutic target in non-small cell lung cancer condition while Juglans mandshurica is a well-studied anticancer plant in some lung cancer cell lines. We intend to find novel exportin-1 inhibitor from Juglans mandshurica with better potential tolerability and pharmaco-dynamo-kinetic properties than the current selective inhibitors of nuclear export in non-small cell lung cancer treatment. Osiris property explorer DataWarrior, Glide standard precision docking, quantum mechanics polarized ligand docking, MMGBSA binding free energy calculations, Jaguar density functional theory analysis, and the online web-based SwissADME were employed respectively in this study to filter the retrieved compounds based on tolerability, toxicity, and Lipinsky’s rule of five violation potential, determine their druggability, establish relative stability of the lead compound in water solvation model, and evaluates druglikeness, lead-likeness, as well as synthetic accessibility of the lead compound. This study reveals eriodictyol as having higher binding free energy (-40 kcal/mol) than that of standard (-39.56 kcal/mol) in exportin-1 active site, better synthetic accessibility score (3.15 versus 3.29), high GI absorption, non-blood brain barrier permeant, lacks Brenk and PAINS alert, obeying Lipinski’s, Ghose’s, Veber’s, Egan’s, and Muegge’s rule of druglikeness and lead-likeness as well as non-cytotoxic to HepG2 cells. We therefore found eriodictyol as a lead-like, non-toxic exportin-1 inhibitor with good predictive stability and pharmacokinetic potential and thus provided data for further validation of eriodictyol as a candidate exportin-1 inhibitor in both preclinical and clinical studies involving lung cancer therapy.

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