New theobromine derivatives inhibiting VEGFR-2: design, synthesis, antiproliferative, docking and molecular dynamics simulations

Hazem A Mahdy; Hazem Elkady; Mohammed S Taghour; Alaa Elwan; Mohammed A Dahab; Mohamed A Elkady; Elsayed Ge Elsakka; Eslam B Elkaeed; Bshra A Alsfouk; Ibrahim M Ibrahim; Ibrahim H Eissa; Ahmed M Metwaly

doi:10.4155/fmc-2023-0089

New theobromine derivatives inhibiting VEGFR-2: design, synthesis, antiproliferative, docking and molecular dynamics simulations

Future Med Chem. 2023 Jul;15(14):1233-1250. doi: 10.4155/fmc-2023-0089. Epub 2023 Jul 19.

Authors

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
² Biochemistry & Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
³ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, 13713, Saudi Arabia.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, PO Box 84428, Riyadh, 11671, Saudi Arabia.
⁵ Biophysics Department, Faculty of Science, Cairo University, Cairo, 12613, Egypt.
⁶ Pharmacognosy & Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, 11884, Egypt.
⁷ Biopharmaceutical Products Research Department, Genetic Engineering & Biotechnology Research Institute, City of Scientific Research & Technological Applications (SRTA-City), Alexandria, 21934, Egypt.

PMID: 37466069
DOI: 10.4155/fmc-2023-0089

Abstract

Background: VEGFR-2 is one of the most effective targets in cancer treatment. Aim: The design and semi-synthesis of new theobromine derivatives as potential VEGFR-2 inhibitors. Methods: In vitro and in silico evaluation of the synthesized compounds. Results: Compound 5b demonstrated excellent antiproliferative and VEGFR-2 inhibitory effects with significant apoptotic activity. It modulated the immune response by increasing IL-2 and reducing TNF-α levels. Docking and molecular dynamics simulations revealed the compound's binding affinity with VEGFR-2. Lastly, computational absorption, distribution, metabolism, excretion and toxicity studies indicated the high potential of compound 5b for drug development. Conclusion: Compound 5b could be a promising anticancer agent targeting VEGFR-2.

Keywords: MD simulations; VEGFR-2; anticancer; apoptosis; immunomodulatory; molecular docking; semisynthesis; theobromine.

Publication types

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

MeSH terms

Antineoplastic Agents* / chemistry
Cell Proliferation
Drug Design
Molecular Docking Simulation
Molecular Dynamics Simulation*
Molecular Structure
Protein Kinase Inhibitors / pharmacology
Structure-Activity Relationship
Theobromine / pharmacology
Vascular Endothelial Growth Factor Receptor-2

Substances

Theobromine
Vascular Endothelial Growth Factor Receptor-2
Protein Kinase Inhibitors
Antineoplastic Agents