Molecular docking and MD simulation studies of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as novel inhibitors targeted to CDK2/4/6 DOI Creative Commons
Jiadong Liang, Yue Zhang, Fei Qin

и другие.

Journal of Cancer Research and Clinical Oncology, Год журнала: 2024, Номер 150(6)

Опубликована: Июнь 10, 2024

Abstract Purpose Nowadays, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for treating metastatic breast cancer and achieved inspiring curative effects. But some discoveries indicated that CDK are not the requisite factors in cell types because CDK2 partly compensates inhibition of CDK4/6. Thus, it is urgent to design CDK2/4/6 significantly enhancing their potency. This study aims explore mechanism binding kinases novel potency different kinds cancers. Materials methods A series 72 disparately functionalized 4-substituted N -phenylpyrimidin-2-amine derivatives exhibiting potent inhibitor activities against CDK2, CDK4 CDK6 were collected apply this research. The total set these was divided into a training (54 compounds) test (18 compounds). constructed through sketch molecule module SYBYL 6.9 software. Powell gradient algorithm Tripos force field used calculate minimal structural energy minimized structure as initial conformation molecular docking. By means 3D-QSAR models, partial least squares (PLS) analysis, dynamics (MD) simulations free calculations, we can find relationship between biological activity. Results In study, docking, simulation comprehensively analyze interaction structure–activity relationships new inhibitors. We detailed statistical data reasonably verify models three receptors (q 2 = 0.714, R pred 0.764, q 0.815; 0.681, 0.757; 0.674). MD decomposition analysis validated reasonability docking results identified polar interactions crucial influence bioactivities studied receptors, especially electrostatic Lys33/35/43 Asp145/158/163. nonpolar with Ile10/12/19 also critical differing potencies concluded following probably enhanced bioactivity kinases: (1) electronegative groups at N1-position electropositive moderate-sized ring E; (2) electrogroups featured ; (3) carbon atoms X-position or C replaced by benzene ring; (4) an electrogroup 4 . Conclusion Previous studies, our knowledge, only utilized single approach did integrate method other sophisticated techniques such discover potential CDK4, CDK6. So applied intergenerational technology, techniques, MMPBSA19/MMGBSA20-binding calculations statistically correlations activities. reasonable confirmed excellent data. hope obtained from work will provide useful references development

Язык: Английский

Computer‐aided design of novel anthranilic diamides containing fluorinated alkoxy groups as potential ryanodine receptor insecticides DOI Open Access
Yue Chen, Jinmin Peng,

Weibin Xie

и другие.

Pest Management Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 29, 2025

Abstract BACKGROUND Increasing the diversity of lead compounds has been shown to enhance efficacy diamide insecticides. Fifty novel were precisely designed and synthesized utilizing fragment‐based assembly virtual screening coupling. RESULTS The median lethal concentration (LC 50 ) values X‐30 X‐40 against Mythimna separata 0.09 0.08 mg L −1 , respectively, which are lower than that chlorantraniliprole (CHL, 0.11 ). Notably, X‐10, X‐18, X‐25, X‐32 X‐43 had corresponding LC 2.0 × 10 −4 5.0 6.0 9.0 7.0 Plutella xylostella respectively. best compound X‐10 exhibited five‐fold greater CHL (1.0 −3 X‐21, X‐29, Spodoptera frugiperda 0.27, 0.26 0.25 slightly (0.33 In case Ostrinia furnacalis showed good with comparable those (1.38 versus 1.57 Calcium imaging experiments demonstrated X‐21 acted on S. ryanodine receptors. Furthermore, this series safety toward nontarget mammals compared CHL. CONCLUSION introduction fluorinated alkoxy groups at 3‐position pyrazole ring leads insecticidal activity improved insect selectivity. © 2025 Society Chemical Industry.

Язык: Английский

Процитировано

0
Molecular Mechanism of λ-Cyhalothrin Detoxification by a Delta-Class Glutathione S-Transferase (PxGSTD3) from Plutella xylostella DOI
Xinyu Li,

Zhouyuan Liu,

Xinxin Lv

и другие.

Journal of Agricultural and Food Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 4, 2025

The diamondback moth (Plutella xylostella) exhibits significant resistance to commonly used insecticides including λ-cyhalothrin. Delta-class glutathione S-transferases (GSTs) are crucial detoxification enzymes involved in insecticide and resistance. We demonstrate that PxGSTD3 is associated with the λ-cyhalothrin contributes detoxification. transcription of was rapidly upregulated response exposure, recombinant protein exhibited metabolic activity against Further investigation using computer-aided drug design revealed binding mechanism toward results showed binds an active pocket through noncovalent interactions such as hydrogen bonds, π-π stacking, hydrophobic interactions. Residues Arg36, Tyr115, Phe119 were found have a critical impact on metabolism by PxGSTD3. These findings provide valuable insights into role GST detoxifying offer theoretical guidance for novel pyrethroid-based insecticides.

Язык: Английский

Процитировано

0
Molecular docking and MD simulation studies of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as novel inhibitors targeted to CDK2/4/6 DOI Creative Commons
Jiadong Liang, Yue Zhang, Fei Qin

и другие.

Journal of Cancer Research and Clinical Oncology, Год журнала: 2024, Номер 150(6)

Опубликована: Июнь 10, 2024

Abstract Purpose Nowadays, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been approved for treating metastatic breast cancer and achieved inspiring curative effects. But some discoveries indicated that CDK are not the requisite factors in cell types because CDK2 partly compensates inhibition of CDK4/6. Thus, it is urgent to design CDK2/4/6 significantly enhancing their potency. This study aims explore mechanism binding kinases novel potency different kinds cancers. Materials methods A series 72 disparately functionalized 4-substituted N -phenylpyrimidin-2-amine derivatives exhibiting potent inhibitor activities against CDK2, CDK4 CDK6 were collected apply this research. The total set these was divided into a training (54 compounds) test (18 compounds). constructed through sketch molecule module SYBYL 6.9 software. Powell gradient algorithm Tripos force field used calculate minimal structural energy minimized structure as initial conformation molecular docking. By means 3D-QSAR models, partial least squares (PLS) analysis, dynamics (MD) simulations free calculations, we can find relationship between biological activity. Results In study, docking, simulation comprehensively analyze interaction structure–activity relationships new inhibitors. We detailed statistical data reasonably verify models three receptors (q 2 = 0.714, R pred 0.764, q 0.815; 0.681, 0.757; 0.674). MD decomposition analysis validated reasonability docking results identified polar interactions crucial influence bioactivities studied receptors, especially electrostatic Lys33/35/43 Asp145/158/163. nonpolar with Ile10/12/19 also critical differing potencies concluded following probably enhanced bioactivity kinases: (1) electronegative groups at N1-position electropositive moderate-sized ring E; (2) electrogroups featured ; (3) carbon atoms X-position or C replaced by benzene ring; (4) an electrogroup 4 . Conclusion Previous studies, our knowledge, only utilized single approach did integrate method other sophisticated techniques such discover potential CDK4, CDK6. So applied intergenerational technology, techniques, MMPBSA19/MMGBSA20-binding calculations statistically correlations activities. reasonable confirmed excellent data. hope obtained from work will provide useful references development

Язык: Английский

Процитировано

1