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Design of Potential Inhibitors and Prediction of their Activity by the Structural Insight of VEGFR2 Inhibitors: Atom‐based 3D‐QSAR, Fingerprint‐based 2D QSAR and Off‐target analysis.
Author(s) -
Rathi Ekta,
Kumar Avinash,
Kini G.
Publication year - 2020
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201903898
Subject(s) - quantitative structure–activity relationship , adme , vegf receptors , herg , chemistry , docking (animal) , computational biology , stereochemistry , pharmacology , combinatorial chemistry , biochemistry , biology , biophysics , in vitro , cancer research , medicine , potassium channel , nursing
VEGF−A is a crucial factor of angiogenesis process in tumor cells. It mediates its biological function through VEGFR2. Therefore, VEGFR2 is a promising target to suppress angiogenesis. Till date, 8‐FDA approved VEGFR2 inhibitors are available but correlated with serious side effects due to off‐target activity of compounds. Hence, these findings alarmed us to find the favorable features of compounds and association of compounds to the serious side effects. To address these question, an Atom‐based 3D and fingerprint‐based 2D QSAR models were constructed. The results of these models assisted us to design the hits 5 a and 6 a with favorable features from the inactive Compound 52 of diaryl urea analogs (IC50=53 μM). The designed hits were subjected for docking, binding free energy calculation, ADME and hERG toxicity in comparison of Compound 52 of diaryl urea analogs. On the contrary to hit 5a and Compound 52 of diaryl urea analogs, hit 6 a possessed crucial interactions with ASP1046 and GLU885 along with acceptable ADMET profile which was affirmed by Molecular Dynamics simulation study. The best hit 6 a was also subjected first time to off‐target analysis employing PoSSuM database.