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GRP78‐targeted in‐silico virtual screening of novel anticancer agents
Author(s) -
Viswanath Ambily Nath Indu,
Lim Ji Woong,
Seo Seon Hee,
Lee Jae Yeol,
Lim Sang Min,
Pae Ae Nim
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13322
Subject(s) - pharmacophore , in silico , virtual screening , chemistry , cancer research , in vitro , docking (animal) , computational biology , pharmacology , biology , stereochemistry , biochemistry , medicine , gene , nursing
Overexpression of GRP78 in a variety of cancers such as glioblastoma, leukemia, lung, prostate, breast, gastric, and colon makes it a prime target for anticancer drug development. Present study reports GRP78‐based design of novel anticancer agents using in‐silico methods. As a first step toward the work, the interactions between GRP78 and 15 known ligands were modeled by docking simulation. The docked complex, GRP78‐ 13 , superior to other compounds with respect to its experimental activity and energy descriptors, was deduced into a structure‐based pharmacophore. This hypothesis was applied as a screening filter to Asinex and Chemdiv databases. Finally, 23 hits were tested in vitro. Among these, VH1019 and VH1011 induced a concentration‐dependent strong broad antiproliferative effect in glioma (U87‐MG), breast cancer (MCF‐7), and prostate cancer (DU‐145) cell lines as compared to nontumorigenic control, neonatal foreskin fibroblast (HFF‐1). These compounds showed preferential growth inhibition of cancer cells over normal cells. The acetohydrazide derivative VH1019 was identified as a potential new chemotype for GRP78 inhibitors with an IC 50 of 12.7 μM in MCF‐7.