| Cyclin-dependent kinase 2(CDK2)belongs to a family of CDKs serine/threonine kinases and is responsible for the regulation of G1/S phase transition process.Clinical studies have found that overexpression of CDK2 leads to tumorigenesis.By inhibiting the expression of CDK2,cell growth can be significantly inhibited,and cells remain in the G1 phase during division,thereby blocking cell proliferation.The central role of CDK2 in controlling mammalian cell cycles and their checkpoints makes it possible to develop therapeutic strategies based on this kinase.With the development of molecular biology and X-ray crystallography,the three-dimensional structure of a large number of disease-related biomacromolecules has been determined.Computer-aided drug design(CADD)has emerged and penetrated into all aspects of new drug research and development,and became one of the core technologies of drug discovery.In general,CADD includes techniques such as structural preparation,molecular docking,molecular dynamics simulation,and binding free energy calculation.In this thesis,by combining these methods,we have analyzed the interactions between CDK2 and its known inhibitors.On the basis of the computational analysis,virtual screening was carried out against CDK2 and four CDK2 inhibitors were successfully discovered.In the first part,the AS-IE method was used to study the binding mode of CDK2 inhibitors,and two modes were found:electrostatic dominated and van der Waals dominated,with the later being the most common mode.Moreover,the hotspot residues in the CDK2-inhibitor interactions were identified,which play a crucial role in the binding.Finally,through the combination of computational virtual screening and ASIE method,20 potential small molecule compounds were selected from a compound library.In vitro kinase inhibition experiments and cell growth experiments were carried out to test these compounds and four of them were found to be active against CDK2. |
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