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Issue 70, 2016, Issue in Progress
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Structure guided design and binding analysis of EGFR inhibiting analogues of erlotinib and AEE788 using ensemble docking, molecular dynamics and MM-GBSA

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Abstract

Epidermal growth factor receptor (EGFR) is an important validated drug target for cancer therapy. Some therapeutic agents targeting EGFR have been developed, however these are sometimes ineffective, which calls for the discovery of alternative novel anti-EGFR inhibitors. Thus, we performed ensemble molecular docking and molecular dynamics (MD) against multiple conformations of EGFR to identify, design and validate new analogs of erlotinib and AEE788 that have enhanced binding affinity. To achieve this, curcumin analogues with diverse groups were studied against EGFR using ensemble molecular docking and MD. Based on the preferred orientations and MM-GBSA calculations of the selected top-scoring consensus lead inhibitors, we derived the pharmacophoric features that possess maximum binding affinity for the EGFR binding site. Using these pharmacophoric properties we designed new analogues of two known co-crystallized therapeutic inhibitors of EGFR (erlotinib and AEE788). We then tested the hypothesis using MD that the identified pharmacophoric property increases binding affinity and increases the stability of the designed analogues. Our MD simulations and MM-GBSA calculations confirmed that the occupancy of sub-pocket 2 in the EGFR active site is important for tight EGFR–inhibitor binding. The study thus provides an essential pharmacophoric requirement for design and discovery of new lead candidates as EGFR inhibitors.

Graphical abstract: Structure guided design and binding analysis of EGFR inhibiting analogues of erlotinib and AEE788 using ensemble docking, molecular dynamics and MM-GBSA

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Publication details

The article was received on 02 Apr 2016, accepted on 04 Jul 2016 and first published on 05 Jul 2016


Article type: Paper
DOI: 10.1039/C6RA08517B
Citation: RSC Adv., 2016,6, 65725-65735
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    Structure guided design and binding analysis of EGFR inhibiting analogues of erlotinib and AEE788 using ensemble docking, molecular dynamics and MM-GBSA

    V. K. Sharma, P. P. Nandekar, A. Sangamwar, H. Pérez-Sánchez and S. M. Agarwal, RSC Adv., 2016, 6, 65725
    DOI: 10.1039/C6RA08517B

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