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Receptor‐guided 3D‐QSAR Study of Anilinoquinazolines as RET Receptor Tyrosine Kinase Antagonists
Author(s) -
Bhujbal Swapnil Pandurang,
Balasubramanian Pavithra Kuruchi,
Keretsu Seketoulie,
Cho Seung Joo
Publication year - 2019
Publication title -
bulletin of the korean chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.237
H-Index - 59
ISSN - 1229-5949
DOI - 10.1002/bkcs.11547
Subject(s) - quantitative structure–activity relationship , steric effects , chemistry , stereochemistry , docking (animal) , kinase , tyrosine kinase , receptor tyrosine kinase , hydrogen bond , piperazine , receptor , biochemistry , medicine , molecule , nursing , organic chemistry
A RET (Rearranged during transfection) kinase belongs to a receptor tyrosine kinase family. It plays a major role in development, maturation, survival, and maintenance of cells and tissues. Oncogenic activation of RET has been reported in numerous cancers. Thus, it is a significant therapeutic target for cancer. Present work covers docking and 3D‐QSAR techniques executed on anilinoquinazoline derivatives as RET kinase antagonists. Docking study recognized important active site amino acid residues like Leu730, Gly731, Gly733, Glu734, Ala807, Gly810, Ser811, and Asp874 which inhibits the RET kinase. In 3D‐QSAR technique, receptor‐guided CoMFA ( q 2 = 0.723, NOC = 5, r 2 = 0.980) as well as CoMSIA ( q 2 = 0.767, NOC = 6, r 2 = 0.967) models were produced. The stabilities of these models were evaluated using diverse validation techniques. Contour maps showed that steric and hydrogen bond donor substitutions are favored at R 1 and R 2 positions whereas positive and negative substitutions are favored at the R 1 position to enhance the potency. In addition, the substitution of H‐bond accepting group to the region which is close to both phenyl and piperazine is favored. Hence, the outcome of this study could be beneficial to design more potent inhibitors for RET kinase.