Receptor-Based Virtual Screening of EGFR Kinase Inhibitors from the NCI Diversity Database

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 the hinge region and the hit compounds are rarely observed. Our results suggest that these molecules could be developed as novel lead compounds in anti-cancer drug design.

Targeting the Epidermal Growth Factor Receptor: Exploring the Potential of Novel Inhibitor N-(3-Ethynylphenyl)-6, 7-bis (2-methoxyethoxy) Quinolin- 4-Amine Using Docking and Molecular Dynamics Simulation

“…The N terminal (Gly695-Gly700) is known to be glycine-rich region involved in nucleotide phosphate-binding, Arg812 Asn818 forms the catalytic loop, Asp831 Gly833 is the C lobe and Asp831 to Val852 is the activation loop. The major residues contributing to binding pocket are: Gly695, Gly700, Lys721, Arg808, Arg812, Asp831, Phe832, Gly833, Lys836, Tyr845, Glu848 and Lys851 [16,42]. These active residues interact with the inhibitors.…”

N4-(3-Bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d]pyrimidines as potent multiple receptor tyrosine kinase inhibitors: Design, synthesis, and in vivo evaluation

“…The binding site of ATP competitive inhibitors in RTKs consists of a Hinge region, two hydrophobic binding sites (Hydrophobic Region I and II) and a Sugar binding pocket (Figure 3). 25,40–42 Compounds 11 and 11a can be seen to adopt different docked conformations in the active site. The pyrrolo[2,3- d ]pyrimidine ring of 11a occupies the adenine binding portion of the ATP binding site.…”

Molecular docking approach to identify potential anticancer compounds from Begonia (Begonia sp)

“…Molecular docking has been successful in discovering novel anticancer compounds against several protein targets, such as BCR-ABL tyrosine kinase, Chk1, FKBP, protein tyrosine phosphatase (PTP) and EGFR as well [1][2][3][4][5]. Epidermal Growth Factor Receptor (EGFR) is a cellular transmembrane glycoprotein that activates tyrosine kinase domain through dimerization to regulate multiple key functions such as cancer cell differentiation, proliferation, survival, and apoptosis.…”