Design, Molecular Modeling, MD Simulations, Essential Dynamics, ADMET, DFT, Synthesis, Anti-proliferative, and Apoptotic Evaluations of a New Anti-VEGFR-2 Nicotinamide Analogue

Ibrahim H Eissa; Eslam B Elkaeed; Hazem Elkady; Reda G Yousef; Bshra A Alsfouk; Heba S A Elzahabi; Ibrahim M Ibrahim; Ahmed M Metwaly; Dalal Z Husein

doi:10.2174/0113816128274870231102114858

Design, Molecular Modeling, MD Simulations, Essential Dynamics, ADMET, DFT, Synthesis, Anti-proliferative, and Apoptotic Evaluations of a New Anti-VEGFR-2 Nicotinamide Analogue

Curr Pharm Des. 2023;29(36):2902-2920. doi: 10.2174/0113816128274870231102114858.

Authors

Ibrahim H Eissa¹, Eslam B Elkaeed², Hazem Elkady¹, Reda G Yousef¹, Bshra A Alsfouk³, Heba S A Elzahabi⁴, Ibrahim M Ibrahim⁵, Ahmed M Metwaly^{6

7}, Dalal Z Husein⁸

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
² Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh 13713, Saudi Arabia.
³ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
⁴ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11884, Egypt.
⁵ Biophysics Department, Faculty of Science, Cairo University, Giza 12613, Egypt.
⁶ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
⁷ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
⁸ Chemistry Department, Faculty of Science, New Valley University, El-Kharja 72511, Egypt.

PMID: 38031271
DOI: 10.2174/0113816128274870231102114858

Abstract

Objectives: This study aims to design and evaluate (in silico and in vitro) a new nicotinamide derivative as an inhibitor of VEGFR-2, a major mediator of angiogenesis Methods: The following in silico studies were performed; DFT calculations, molecular modelling, MD simulations, MM-GBSA, PLIP, and PCAT studies. The compound's in silico (ADMET) analysis was also conducted. Subsequently, the compound ((E)-N-(4-(1-(2-(4-(4-Chlorobenzamido)benzoyl)hydrazono)ethyl) phenyl)nicotinamide) was successfully synthesized and designated as compound X. In vitro, VEGFR-2 inhibition and cytotoxicity of compound X against HCT-116 and A549 cancer cell lines and normal Vero cell lines were conducted. Apoptosis induction and migration assay of HCT-116 cell lines after treatment with compound X were also evaluated.

Results: DFT calculations assigned stability and reactivity of compound X. Molecular docking and MD simulations indicated its excellent binding against VEGFR-2. Furthermore, MM-GBSA analysis, PLIP experiments, and PCAT studies confirmed compound X's correct binding with optimal dynamics and energy. ADMET analysis expressed its general likeness and safety. The in vitro assays demonstrated that compound X effectively inhibited VEGFR-2, with an IC₅₀ value of 0.319 ± 0.013 μM and displayed cytotoxicity against HCT-116 and A549 cancer cell lines, with IC₅₀ values of 57.93 and 78.82 μM, respectively. Importantly, compound X exhibited minimal toxicity towards the non-cancerous Vero cell lines, (IC₅₀ = 164.12 μM). Additionally, compound X significantly induced apoptosis of HCT-116 cell lines and inhibited their potential to migrate and heal.

Conclusion: In summary, the presented study has identified compound X as a promising candidate for the development of a novel apoptotic lead anticancer drug.

Keywords: DFT; MD simulations; Nicotinamide derivative; PCAT.; VEGFR-2; anticancer.

Publication types

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

MeSH terms

A549 Cells
Antineoplastic Agents* / pharmacology
Cell Proliferation
Drug Screening Assays, Antitumor
HCT116 Cells
Humans
Molecular Docking Simulation
Molecular Structure
Niacinamide / pharmacology
Protein Kinase Inhibitors
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2*

Substances

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

Grants and funding

PNURSP2023R142/Princess Nourah Bint Abdulrahman University