Discovery of New VEGFR-2 Inhibitors: Design, Synthesis, Anti-Proliferative Evaluation, Docking, and MD Simulation Studies

Eslam B Elkaeed; Reda G Yousef; Mohamed M Khalifa; Albaraa Ibrahim; Ahmed B M Mehany; Ibraheem M M Gobaara; Bshra A Alsfouk; Wagdy M Eldehna; Ahmed M Metwaly; Ibrahim H Eissa; Mohamed Ayman El-Zahabi

doi:10.3390/molecules27196203

Discovery of New VEGFR-2 Inhibitors: Design, Synthesis, Anti-Proliferative Evaluation, Docking, and MD Simulation Studies

Molecules. 2022 Sep 21;27(19):6203. doi: 10.3390/molecules27196203.

Authors

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia.
² Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
³ Zoology Department, Faculty of Science (Boys), Al-Azhar University, Cairo 11884, Egypt.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt.
⁶ School of Biotechnology, Badr University in Cairo, Badr City 11829, Egypt.
⁷ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
⁸ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt.

Abstract

Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners were synthesized possessing the pharmacophoric essential features to bind correctly with the VEGFR-2 active pocket. All members were evaluated for their cytotoxic and VEGFR-2 inhibitory potentialities. Compound 6 was the most potent showingIC₅₀ values of 9.3 ± 0.02 and 7.8 ± 0.025 µM against HCT-116 and HepG-2 cells, respectively, and IC₅₀ of 60.83 nM regarding VEGFR-2 enzyme inhibition. Compound 6 arrested the growth of HCT-116 cells at the pre-G1 and G2-M phases. Further, it induced both early and late apoptosis. Additionally, compound 6 caused a significant decrease in TNF-α and IL6 by 66.42% and 57.34%, respectively. The considered compounds had similar docking performances to that of sorafenib against the VEGFR-2 (PDB ID: 2OH4). The correct binding of compound 6 with VEGFR-2 was validated using MD simulations, and MM-GPSA calculations.

Keywords: MD simulations; VEGFR-2 inhibitors; anti-proliferative; apoptosis; immunomodulation; nicotinamide.

MeSH terms

Antineoplastic Agents* / chemistry
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Interleukin-6 / pharmacology
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemistry
Sorafenib / pharmacology
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / pharmacology
Vascular Endothelial Growth Factor Receptor-2*

Substances

Antineoplastic Agents
Interleukin-6
Protein Kinase Inhibitors
Tumor Necrosis Factor-alpha
Sorafenib
Vascular Endothelial Growth Factor Receptor-2

Grants and funding

PNURSP2022R142/Princess Nourah bint Abdulrahman University