Investigation of the structural and physicochemical requirements of quinoline-arylamidine hybrids for the growth inhibition of K562 and Raji leukemia cells

Authors : Vesna RASTIJA, Marijana JUKIC, Teuta OPACAKBERNARDI, Luka KRSTULOVIC, İvana STOLIC, Ljubica GLAVACOBROVAC, Miroslav BAJIC

Pages : 251-265

View : 11 | Download : 6

Publication Date : 0000-00-00

Article Type : Research Paper

Abstract :Quantitative structure-activity relationship insert ignore into journalissuearticles values(QSAR); analysis of 28 quinoline-arylamidine insert ignore into journalissuearticles values(CQArA); hybrids against two leukemia cells, K562 and Raji, was performed. Multiple linear regression insert ignore into journalissuearticles values(MLR); models were obtained by genetic algorithm. The best models involved the following descriptors: radial distribution function insert ignore into journalissuearticles values(RDF); descriptors, GETAWAY insert ignore into journalissuearticles values(GEometry, Topology, and Atom-Weights AssemblY); descriptor, bond information content index, and dipole moment. The best MLR models for K562 and Raji cells demonstrated satisfactory stability in internal and external validation. Since the QSAR model for Raji cells has better predictive ability, two new highly potent CQArA analogues were proposed based on it. The QSAR models revealed important physicochemical and structural requirements for the antitumor activity: enhanced 3D molecular distribution of mass calculated at radius 11 Å from the center of molecule, a higher number of terminal electronegative atoms, extension of the molecules` central linker between quinoline and arylamidine, higher ratio of single bonds and total number of atoms, and symmetric charge distribution. Molecular docking study was applied to ensure the anticancer activity affinity to the binding site of the tyrosine-protein kinase insert ignore into journalissuearticles values(c-SRC);. It was confirmed that the most active compound binds on the pocket between the small and large lobes of c-SRC, mostly throughout the hydrogen bonds and van der Waals interactions.
Keywords : Structure activity, molecular docking, hybrid anticancer drugs, leukemia