Anticancer derivative of the natural alkaloid, theobromine, inhibiting EGFR protein: Computer-aided drug discovery approach

Ibrahim H Eissa; Reda G Yousef; Eslam B Elkaeed; Aisha A Alsfouk; Dalal Z Husein; Ibrahim M Ibrahim; Mohamed S Alesawy; Hazem Elkady; Ahmed M Metwaly

doi:10.1371/journal.pone.0282586

Anticancer derivative of the natural alkaloid, theobromine, inhibiting EGFR protein: Computer-aided drug discovery approach

PLoS One. 2023 Mar 9;18(3):e0282586. doi: 10.1371/journal.pone.0282586. eCollection 2023.

Authors

Ibrahim H Eissa¹, Reda G Yousef¹, Eslam B Elkaeed², Aisha A Alsfouk³, Dalal Z Husein⁴, Ibrahim M Ibrahim⁵, Mohamed S Alesawy¹, Hazem Elkady¹, Ahmed M Metwaly^{6

7}

Affiliations

¹ Faculty of Pharmacy (Boys), Pharmaceutical Medicinal Chemistry & Drug Design Department, 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 Faculty of Science, Chemistry Department, New Valley University, El-Kharja, Egypt.
⁵ Faculty of Science, Biophysics Department, Cairo University. Cairo, Egypt.
⁶ Faculty of Pharmacy (Boys), Pharmacognosy and Medicinal Plants Department, Al-Azhar University, Cairo, Egypt.
⁷ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.

Abstract

A new semisynthetic derivative of the natural alkaloid, theobromine, has been designed as a lead antiangiogenic compound targeting the EGFR protein. The designed compound is an (m-tolyl)acetamide theobromine derivative, (T-1-MTA). Molecular Docking studies have shown a great potential for T-1-MTA to bind to EGFR. MD studies (100 ns) verified the proposed binding. By MM-GBSA analysis, the exact binding with optimal energy of T-1-MTA was also identified. Then, DFT calculations were performed to identify the stability, reactivity, electrostatic potential, and total electron density of T-1-MTA. Furthermore, ADMET analysis indicated the T-1-MTA's general likeness and safety. Accordingly, T-1-MTA has been synthesized to be examined in vitro. Intriguingly, T-1-MTA inhibited the EGFR protein with an IC50 value of 22.89 nM and demonstrated cytotoxic activities against the two cancer cell lines, A549, and HCT-116, with IC50 values of 22.49, and 24.97 μM, respectively. Interestingly, T-1-MTA's IC50 against the normal cell lines, WI-38, was very high (55.14 μM) indicating high selectivity degrees of 2.4 and 2.2, respectively. Furthermore, the flow cytometry analysis of A549 treated with T-1-MTA showed significantly increased ratios of early apoptosis (from 0.07% to 21.24%) as well as late apoptosis (from 0.73% to 37.97%).

Copyright: © 2023 Eissa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Proliferation
Drug Discovery
Drug Screening Assays, Antitumor
ErbB Receptors / metabolism
Molecular Docking Simulation
Protein Kinase Inhibitors / chemistry
Structure-Activity Relationship
Theobromine* / pharmacology

Substances

Theobromine
Antineoplastic Agents
ErbB Receptors
Protein Kinase Inhibitors

Grants and funding

This research was funded by Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2023R116), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors extend their appreciation to the Research Center at AlMaarefa University for funding this work.