Perpustakaan Digital ITB

Breast cancer is one of the deadliest cancers that commonly occurs in women, coming as a second rank after lung cancer. There have been many advances in the drug treatment to combat the breast cancer –one of them is by inhibiting cyclin-dependent kinases (CDK) as they play important roles in the eukaryotic cell cycle progression. There are many kinds of cyclin-dependent kinases, and CDK2 is one of them. A research showed that the pyrimidine derivatives are potentially able to induce apoptosis in MDA-MB-468 cells by inhibiting CDK2. The aim of this research was to design new pyrimidine derivatives as potential anticancer agents based on Quantitative Structure-Activity Relationship (QSAR) method. The structure of 24 pyrimidine derivatives were prepared and optimized using Gaussian09 to obtain their stable conformations. The physicochemical properties, or descriptors, were calculated using Gaussian09 and Molecular Operating Environment 2014.0901. Then, the statistical analysis was performed to determine the best QSAR model by using multilinear regression on SPSS Statistics 26 and the validation of model was done using Leave One Out method. Novel pyrimidine derivatives were designed using Topliss scheme based on valid QSAR equation. Structure-based interaction study between pyrimidine derivatives against CDK2 (PDB ID: 1PYE) was conducted by molecular docking simulation using AutoDock 4.2 and MGLTools 1.5.6 software. The QSAR equation obtained from this study was Log(1/IC50) = ?19.34200 ?35.82030 × (HOMO) + 33.13616 × (LUMO) ?0.01592 × (ASA_H) + 0.02356 × (vol) + 0.06555 × (E_vdw) + 12.46394 × (density). Based on this QSAR equation, 6 compounds were predicted to have better IC50 value towards CDK2 than the lead compound. These 6 compounds were docked into CDK2 and the docking result showed that 3 compounds have better free binding energy than the lead compound. In conclusion, compound 25, 26, and 27 were predicted have better anticancer activity than the lead compound and it can be a potential novel pyrimidine derivatives as CDK2 inhibitors.