2. Academic Validation
  3. Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer

Computer-Assisted Drug Discovery of a Novel Theobromine Derivative as an EGFR Protein-Targeted Apoptosis Inducer

  • Evol Bioinform Online. 2023 Dec 1:19:11769343231217916. doi: 10.1177/11769343231217916.
Ibrahim H Eissa 1,  Reda G Yousef 1,  Eslam B Elkaeed 2,  Aisha A Alsfouk 3,  Dalal Z Husein 4,  Ibrahim M Ibrahim 5,  Hesham A El-Mahdy 6,  Hazem Elkady 1,  Ahmed M Metwaly 7 8
Affiliations

Affiliations

  • 1 Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
  • 3 Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
  • 4 Chemistry Department, Faculty of Science, New Valley University, El-Kharja, Egypt.
  • 5 Biophysics Department, Faculty of Science, Cairo University. Cairo, Egypt.
  • 6 Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
  • 7 Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
  • 8 Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
PMID: 38046652 DOI: 10.1177/11769343231217916
Abstract

The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in Cancer treatment, with the aim of reducing its proliferation and inducing Apoptosis. This study aimed at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative (T-1-DOCA). Firstly, T-1-DOCA's total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of T-1-DOCA against wild and mutant EGFR proteins. T-1-DOCA's correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, T-1-DOCA showed noticeable efficacy compared to erlotinib by suppressing EGFRWT and EGFRT790M with IC50 values of 56.94 and 269.01 nM, respectively. T-1-DOCA inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC50 values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its Anticancer potential and general safety. The apoptotic effects of T-1-DOCA were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of Bax, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, T-1-DOCA, a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that T-1-DOCA is a promising candidate for further development as an anti-cancer drug.

Keywords

ED; EGFR inhibitors; MD simulation; Semi synthesis; anti-proliferative; apoptosis; docking.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z