QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF BIPHENYLUREA DERIVATIVES AS INHIBITOR OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-2

• Main Author: Ching Ying, Jan
• Format: Final Project
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/36990
• Institution: Institut Teknologi Bandung

Biphenylurea derivatives can be used as tyrosine-kinase inhibitors (TKI). Tyrosine kinase is an enzyme which has a role of activation of signal transduction cascades of various proteins. TKI inhibits the phosphorylation of activated proteins. The activation of vascular endothelial growth factor receptor2 (VEGFR-2) is an important step for signal transduction pathway which starts tumor angiogenesis. The biphenylurea derivative was made up of the combination of two drugs which are Sorafenib and Pazopanib. These two drugs have are used as treatment of advanced renal cell carcinoma. The aim of this study is to express the descriptors involved in determination of activity of biphenylurea derivatives towards the VEGFR-2 receptor and to design a new derivatives based on Quantitative Structure Activity Relationship (QSAR) methods. The designing and optimization of molecular structure was done using Gauss View 5.0.8 and Gaussian 09W software. The calculation of descriptor value and multilinear regression statistics were each performed using MOE 2009.10 and SPSS Statistics 21.0. The QSAR equation with the highest q2 value was obtained through validation test using Leave One Out (LOO) method. The designing of the new compounds were designed by using Topliss Scheme and Craig Plot according to the QSAR equation. Docking of newly designed compounds into tyrosine kinase enzyme were conducted using AutoDock 4.2 software to determine the interactions. The QSAR equation acquired was Log IC50 = 2.111 – (8.847 x 10-6) AM1_Eele + 0.015 (±0.006) HF – 32.732 (±5.612) glob + 0.0511 (±0.227) log P – 10.164 (±2.286) mr + 0.274 (±0.60) vol. The result shows that only 5 new compounds have predicted IC50value lower than that of parent compound based in QSAR equation. There are three new derivatives that have better result of free binding energy. The best new derivative was compound 1e which can be used for further studies.