Comparative binding affinity analysis of dual CDK2/FLT3 inhibitors

다국어 초록 (Multilingual Abstract)

Selective inhibition of cyclin-dependent kinase 2 (CDK2) using small molecules is gaining popularity for the treatment of certain types of acute myeloid leuke- mia (AML). In this study, we used different molecular modeling techniques to investigate the structure–activity relationship (SAR) and binding modalities of dual CDK2/FLT3 inhibitors. The key chemical characteristics of the 3H-pyrazolo [4,3-f]quinoline derivatives were highlighted as descriptive colored contours using comparative molecular similarity analysis (CoMSIA). Modifying chemical groups in existing compounds along these contours could improve CDK2 selec- tivity over FMS-like tyrosine kinase 3 (FLT3). We determined the ligand affinities for CDK2 by estimating the binding free energy using molecular mechanics generalized Born surface area (MM-GBSA) and umbrella sampling (US) simulations. Reasonable correlations were found between the computed and experimental binding energies, suggesting that MM-GBSA and US can be used to reliably predict the binding affinities of new compounds in the more potent CDK2 drug development process.

참고문헌 (Reference)

1 R. Drula, 100971-, 2022

2 O. Méndez-Lucio, 2 (2): 1058-, 2011

3 A. Singh, 30 (30): 897-, 2022

4 W. Bazzar, 20 (20): 23-, 2021

5 L. Wang, 17 (17): 567-, 2021

6 W. Chantkran, 7 (7): 1-, 2021

7 A. E. Osman, 49 : 100825-, 2021

8 M. Salemizadeh Parizi, 29 (29): 1613-, 2021

9 S. Chen, 13 (13): 13640-, 2021

10 A. L. Nazarova, 12 (12): e766-, 2022

11 N. Dayal, 64 (64): 10981-, 2021

12 M. M. Reif, 2385 : 255-, 2022

13 J. P. Bewersdorf, 36 (36): 259-, 2022

14 M. S. Valdés-Tresanco, 17 (17): 6281-, 2021

15 A. W. S. Da Silva, 5 (5): 1-, 2012

16 S. Ghosh, 23 (23): 7696-, 2022

17 S. Ghosh, 22 (22): 12511-, 2021

18 S. Ghosh, 9 : e11951-, 2021

19 C. G. Gadhe, 38 (38): 861-, 2012

20 C. G. Gadhe, 11 (11): 5-, 2011

21 A. A. San Juan, 13 (13): 601-, 2007

22 Z. Yang, 179 (179): 269-, 2012

23 S. Ghosh, 10 (10): 813-, 2022

24 D. Van Der Spoel, 26 (26): 1701-, 2005

25 R. Huey, "Using AutoDock 4 With AutoDocktools: A Tutorial, Vol. 8" The Scripps Research Institute 54-, 2008

26 Ghosh Suparna ; Cho Seung Joo, "Structure–activity relationship and in silico development of c-Met kinase inhibitors" 대한화학회 43 (43): 882-892, 2022

27 Suparna Ghosh ; Seketoulie Keretsu ; Seung Joo Cho, "Computational Modeling of Novel Phosphoinositol-3-kinase γ Inhibitors Using Molecular Docking, Molecular Dynamics, and 3D-QSAR" 대한화학회 42 (42): 1093-1111, 2021

28 S. T. Ngo, "Computational Methods for Estimating the Kinetic Parameters of Biological Systems" Springer 313-, 2022

29 고스 수팔나 ; Seketoulie Keretsu ; 조승주, "3D-QSAR, Docking and Molecular Dynamics Simulation Study of C-Glycosylflavones as GSK-3β Inhibitors" 기초과학연구원 13 (13): 170-180, 2020