QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDY OF 4-(PYRAZOL-4-YL)-PYRIMIDINE DERIVATIVES WHICH INHIBIT CYCLIN-DEPENDENT KINASE (CDK)2 AND CDK4/6

• Main Author: Akrimah
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/45377
• Institution: Institut Teknologi Bandung

4-(Pyrazol-4-yl)-pyrimidine derivatives have anticancer activity by acting as inhibitor of cyclin-dependent kinase (CDK)1/2 and CDK4/6. CDK is a protein kinase which involved in controlling cell cycle, regulating transitions of one phase to another. Inhibition of CDK2 led to apoptosis, while inhibition of CDK4/6 prevent phophorylation of pRb at rapid growth G1 stage of cell cycle. A selective CDK inhibitor is an important factor to increase therapy effectivity. The aim of the research is to obtain the QSAR equations of the 4-(pyrazol-4-yl)-pirimidine derivatives towards CDK receptors, and design new derivatives with higher activity and selectivity compared to the parent compound [4-(5-chloro-3- isopropyl- 1H -pyrazol-4-yl- pyrimidin-2-yl]- (5-piperazin-1-yl-pyridin-2-yl) - amine. This research used several softwares. Modeling and optimization of the geometry structures were done by Gaussian software. Calculation of desciptors value and multilinear statistical analysis were performed by MOE 2009.10 and SPSS Statistics 17.0, respectively. The results were then validated by LOO (Leave One Out) method to obtain the QSAR equation with the highest q 2 . The selectivity of the new designed compunds were compared to the parent compound and were then docked to the CDK receptors using Arguslab 4.0.1. The QSAR equations are log IC50CDK2 : 1.893118(±0.982) –0.000033586 (±0.000004609) AM1_E – 0.0243789 (±0.0079434) ASA_H + 1.0215018(±0.391092) mr, logIC50CDK4 : 0.5346468 (±0.9034229) + 0.0000171273 (±0.000006652) AM1_E + 0.013911(±0.0066072) ASA_H –0.224181 (±0.0769281) polarizability. [4-(5,3- Ditrifluoromethyl-1H- pyrazol-4-yl)- pyrimidin-2-yl]- (5-piperazin-1-yl-pyridin2-yl)-amine was the compound with the highest selectivity to CDK4, 9035.23 fold compared to CDK2. This compound had spontaneous interaction with CDK2 and CDK6, homolog of CDK4, and formed hydrogen bonding with His84 and Gln85 residues of CDK2, which affects its selectivity.