Receptor-based virtual screening of EGFR kinase inhibitors from the NCI diversity database.

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Kiattawee ChoowongkomonJumras Limtrakul

Abstract

Epidermal growth factor receptor (EGFR) abnormalities have been associated with several types of human cancer. The crystal structures of its tyrosine kinase domain (EGFR-TK) complexed with small molecule inhibitors revealed the kinase inhibition modes, prompting us to search for novel anti-cancer drugs. A total of 1,990 compounds from the National Cancer Institute (NCI) diversity set with nonredundant structures have been tested to inhibit cancer cell lines with unknown mechanism. Cancer inhibition through EGFR-TK is one of the mechanisms of these compounds. In this work, we performed receptor-based virtual screening against the NCI diversity database. Using two different docking algorithms, AutoDock and Gold, combined with subsequent post-docking analyses, we found eight candidate compounds with high scoring functions that all bind to the ATP-competitive site of the kinase. None of these compounds belongs to the main group of the currently known EGFR-TK inhibitors. Binding mode analyses revealed that the way these compounds complexed with EGFR-TK differs from quinazoline inhibitor binding and the interaction mainly involves hydrophobic interactions. Also, the common kinase-inhibitor (NH---N and CO---HC) hydrogen bonds between ...Continue Reading

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Citations

Oct 25, 2011·PLoS Computational Biology·Shun-Chieh YangCalvin Yu-Chian Chen
Nov 13, 2012·European Journal of Medicinal Chemistry·Samar MowafyKhaled A M Abouzid
Jul 10, 2020·Journal of Biomolecular Structure & Dynamics·Bhavana JonnalagaddaAbhinand P A
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Oct 1, 2020·Biomolecules·Ebrahim Rahmani MoghadamAlan Prem Kumar
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Aug 28, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Yuan LiangJie Zhang
Oct 1, 2021·The Protein Journal·Preantha PoonanMahmoud E S Soliman

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Methods Mentioned

BETA
antisense oligonucleotides
X-ray

Software Mentioned

pmol2q script
Screenscore
ChemScore
OpenBabelGUI
VIDA
FRED
AutoDock
splitmol2
Piecewise
PyMol

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