Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking

Future Medicinal Chemistry
Fabiana CaporuscioGiulio Rastelli

Abstract

The EGFR inhibitors represent the first-line treatment of non-small-cell lung cancer. However, the emergence of resistance urgently requires the development of new inhibitors targeting drug-resistant mutants. A recently released structure of an EGFR kinase domain in complex with an allosteric inhibitor and a mutant protein model derived from it were used to set up a low-cost high-throughput docking protocol for the fast identification of EGFR allosteric inhibitors. The virtual screening of commercially available compounds led to the identification of interesting new hit compounds. The most promising hit was confirmed to be a new allosteric inhibitor of wild-type and T790M/L858R double mutant EGFR which was able to inhibit the growth of  non-small-cell lung cancer cell lines.

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Citations

Jul 16, 2020·Pharmacological Reports : PR·Swastika MaityYogendra Nayak
Jul 22, 2018·Future Medicinal Chemistry·Chérif F Matta, Michael C Hutter
Nov 7, 2019·Journal of Medicinal Chemistry·Harald EngelhardtDarryl B McConnell

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Methods Mentioned

BETA
NMR
Assay

Software Mentioned

RDKit
LigPrep
Glide SP
Epik
Schr
Protein Preparation Wizard
PROPKA
dinger Suite

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