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

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 IC ₅₀ value of 0.319 ± 0.013 μM and displayed cytotoxicity against HCT-116 and A549 cancer cell lines, with IC ₅₀ values of 57.93 and 78.82 μM, respectively. Importantly, compound X exhibited minimal toxicity towards the non-cancerous Vero cell lines, (IC ₅₀ = 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.
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