Computational studies of potent covalent inhibitors on wild type or T790M/L858R mutant epidermal growth factor receptor.

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Zichao YangTingting Zhang

Abstract

In this paper, we designed and synthesized two analog compounds M1 and T1 that have a Michael acceptor warhead. Although only slightly diversity existed in the structures of M1 and T1, their inhibitory activities against wild type epidermal growth factor receptor (EGFRWT) and T790M/L858R mutant epidermal growth factor receptor (EGFRT790M/L858R) were significant different. Thus, multiple computational approaches were applied to investigate the interactions between the compounds with EGFRWT and EGFRT790M/L858R in order to explore the effect of different compounds. The molecular docking and MD simulations were performed to study the intermolecular interactions between compounds and EGFR. The binding free energy revealed that M1-EGFRWT and M1-EGFRT790M/L858R complexes have stronger binding affinity compared with the corresponding T1-EGFRWT and T1-EGFRT790M/L858R complexes, respectively. And the binding free energy decompositions for each residue analysis indicated that the van der Waals interactions are the major contributor to enhance the compounds to bind with EGFR. In addition, covalent binding complexes of M1-EGFRWT and M1-EGFRT790M/L858R were constructed and studied. Moreover, quantum mechanics method was applied to investigat...Continue Reading

References

Sep 15, 1988·Physical Review A: General Physics·A D Becke
Feb 24, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Martin H CohenRichard Pazdur
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
May 4, 2004·Nature Reviews. Cancer·Andreas GschwindAxel Ullrich
Apr 16, 2005·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Jinru ShiaBeiyun Chen
Jan 20, 2006·Journal of Medicinal Chemistry·Woody ShermanRamy Farid
Feb 10, 2007·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiaoyan WangLiang Cheng
Feb 24, 2007·Nature Reviews. Cancer·Sreenath V SharmaDaniel A Haber
Apr 13, 2007·Journal of Chemical Information and Modeling·Karen L SchuchardtTheresa L Windus
Jan 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Cai-Hong YunMichael J Eck
Mar 14, 2008·The New England Journal of Medicine·Fortunato Ciardiello, Giampaolo Tortora
May 9, 2009·Journal of Oncology·Amir HarandiDamian A Laber
Dec 25, 2009·Nature·Wenjun ZhouPasi A Jänne
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
Jun 10, 2010·Drug Design, Development and Therapy·M TiseoP Bordi
Mar 9, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Helena A YuGregory J Riely
Dec 19, 2013·Proceedings of the National Academy of Sciences of the United States of America·Phillip A SchwartzBrion William Murray
Jun 12, 2014·Journal of Chemical Information and Modeling·Kai ZhuEdward Harder
Feb 6, 2015·CA: a Cancer Journal for Clinicians·Lindsey A TorreAhmedin Jemal
Aug 28, 2015·European Journal of Medicinal Chemistry·Long ZhangChuanwen Fan
Oct 13, 2015·Journal of Medicinal Chemistry·Robert HealdTimothy P Heffron
Nov 3, 2015·Journal of Structural Biology·Yuliana YosaatmadjaChristopher J Squire
Mar 13, 2016·Bioorganic & Medicinal Chemistry Letters·Hengmiao ChengBrion W Murray
Apr 14, 2016·Journal of Hematology & Oncology·Shuhang WangDelong Liu
Oct 17, 2017·Drug Discovery Today·Mahaveer Singh, Hemant R Jadhav

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