An in silico exploration of the interaction mechanism of pyrazolo[1,5-a]pyrimidine type CDK2 inhibitors
Li, Yan1; Gao, Weimin1; Li, Feng2; Wang, Jinghui1; Zhang, Jingxiao1; Yang, Yinfeng1; Zhang, Shuwei1; Yang, Ling3
Indexed BySCI
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS SubjectBiochemistry & Molecular Biology
WOS Research AreaBiochemistry & Molecular Biology
AbstractCDK2, which interacts with cyclin A and cyclin E, is an important member of the CDK family. Having been proved to be associated with many diseases for its vital role in cell cycle, CDK2 is a promising target of anti-cancer drugs dealing with cell cycle disorders. In the present work, a total of 111 pyrazolo[1,5-a]pyrimidines (PHTPPs) as CDK2/cyclin A inhibitors were studied to conduct three-dimensional quantitative structure-activity (3D-QSAR) analyses. The optimal comparative molecular similarity indices analysis (CoMSIA) model shows that Q(2) = 0.516, R-ncv(2) = 0.912, R-pre(2) = 0.914, R-m(2) = 0.843, SEP = 0.812, SEE = 0.347 with 10 components using steric, hydrophobic and H-bond donor field descriptors, indicating its effective internal and external predictive capacity. The contour maps further indicate that (1) bulky substituents in R-1 are beneficial while H-bond donor groups at this position are detrimental; (2) hydrophobic contributions in the R-2 area are favorable; (3) large and hydrophilic groups are well tolerated at the R-3 position (a close H-bond donor moiety is favorable while a distal H-bond donor moiety in this area is disfavored); (4) bulky and hydrophobic features in the R-4 region are beneficial for the biological activities and (5) the 7-N-aryl substitution is crucial to boost the inhibitory activities of the PHTPP inhibitors. Finally, docking and MD simulations demostrate that PHTPP derivatives are stabilized in a 'flying bat' conformation mainly through the H-bond interactions and hydrophobic contacts. Comparative studies indicate that PHTPP derivatives fit well within the ATP binding cleft in CDK2, with the core heterocyclic ring overlapping significantly with the adenine group of ATP despite a small deflection. In comparison to numerous other inhibitors binding to the ATP pocket, PHTPP analogues follow the binding fashion of purine inhibitors of this kinase. It is anticipated that the binding mechanism and structural features of PHTPP inhibitors studied in the present work will benefit the discovery of more potent CDK2 inhibitors, and the valid pyrazolo[1,5-a]pyrimidine-7-N-yl inhibitors will soon emerge from the large number of screening programmes to enter in clinical studies.
WOS IDWOS:000322447600009
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Cited Times:11[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Affiliation1.Dalian Univ Technol, MOE, Key Lab Ind Ecol & Environm Engn, Dalian 116024, Liaoning, Peoples R China
2.Henan Inst Engn, Dept Civil Engn, Zhengzhou 451191, Henan, Peoples R China
3.Chinese Acad Sci, Grad Sch, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian 116023, Liaoning, Peoples R China
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GB/T 7714
Li, Yan,Gao, Weimin,Li, Feng,et al. An in silico exploration of the interaction mechanism of pyrazolo[1,5-a]pyrimidine type CDK2 inhibitors[J]. MOLECULAR BIOSYSTEMS,2013,9(9):2266-2281.
APA Li, Yan.,Gao, Weimin.,Li, Feng.,Wang, Jinghui.,Zhang, Jingxiao.,...&Yang, Ling.(2013).An in silico exploration of the interaction mechanism of pyrazolo[1,5-a]pyrimidine type CDK2 inhibitors.MOLECULAR BIOSYSTEMS,9(9),2266-2281.
MLA Li, Yan,et al."An in silico exploration of the interaction mechanism of pyrazolo[1,5-a]pyrimidine type CDK2 inhibitors".MOLECULAR BIOSYSTEMS 9.9(2013):2266-2281.
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