QSAR, Design, and Molecular Docking of Potential Anti-Cancer Chromene-Dione Derivatives
H. A. Aziz, W. P. Nirwani, C. P. Putra, H. Hendrawan

Chemistry Study Program, Indonesia University of Education

Abstract

Cancer, which happened due to error in cell replication is one of the deadliest diseases in the world. In this study, we performed a Quantitative Structure-Activity Relationship study of Chromene-Dione derivatives as potential anti-cancer drug based on H1229 cell line test, designed some new Chromene-Dione derivatives with better predicted activity, and performed molecular docking calculation to predicts its interaction with the receptor protein.

QSAR equation search is performed using genetic algorithm on BuildQSAR software on optimized structure of the compounds. The geometry optimization is performed on Orca 4.2.1 using DFT/B3LYP/6-31G methods. Molecular docking calculation is performed using genetic algorithm on AutoDock 4 software, and the calculation results is visualized using Biovia Discovery Studio.

QSAR equation search resulting is 5 equations that is considered to be robust enough to be used in designing new compounds. One of the equations is:

\[logIC_{50}=-0.0012\left(\pm0.0002\right)TDB7m+0.0007(\pm0.0003)TDB8m-0.0134(\pm0.0052)RDF35e-1.6834\left(\pm0.6028\right)E2v+0.9843\left(\pm0.3257\right)E3v+2.1491\left(\pm0.2351\right)\]

Based on those 5 equations, we designed several compounds, 2 of which produced activity that is better than the best compound in the data set, thus indicating new potential compounds. To see the possible interaction with protein, we performed molecular docking calculation with 3 receptors which are AKT1 (PDB ID: 3MV5), EYA2 (PDB ID: 5ZMA), and EGFR (PDB ID: 1M17). Molecular docking calculation show that all 6 complexes indicating similar interaction with the native ligand, with one complex in particular (C14-AKT1) has lower energy (-7.61 kcal/mole) than the reference native complex of XFE-AKT1 (-7.51 kcal/mole) with acceptable RMSD.

Keywords: QSAR, Molecular Docking, Anticancer, Chromene-Dione Derivatives

Topic: Theoretical and Computational Chemistry