Journal Article

Design, Synthesis, Docking, DFT, MD Simulation Studies of a New Nicotinamide-Based Derivative: In Vitro Anticancer and VEGFR-2 Inhibitory Effects

Yousef, Reda G., Gobaara, Ibraheem M. M., Alsfouk, Bshra A., Husein, Dalal Z., Elkaeed, Eslam B., Ibrahim, Ibrahim M., Eissa, Ibrahim H., Elkady, Hazem, Metwaly, Ahmed M.

2022

Overview

A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact with the VEGFR-2 catalytic pocket. The ability of the designed congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, to bind with the VEGFR-2 enzyme was demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established the excellent binding of compound 10 with VEGFR-2 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed the proper binding with a total exact binding energy of −38.36 Kcal/Mol. MM-GBSA studies also revealed the crucial amino acids in the binding through the free binding energy decomposition and declared the interactions variation of compound 10 inside VEGFR-2 via the Protein–Ligand Interaction Profiler (PLIP). Being new, its molecular structure was optimized by DFT. The DFT studies also confirmed the binding mode of compound 10 with the VEGFR-2. ADMET (in silico) profiling indicated the examined compound’s acceptable range of drug-likeness. The designed compound was synthesized through the condensation of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group. The in-vitro studies were consonant with the obtained in silico results as compound 10 prohibited VEGFR-2 with an IC50 value of 51 nM. Compound 10 also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC50 values of 8.25 and 6.48 μM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively.

• Publisher: MDPI AG,MDPI
• Subject: Amino acids / Angiogenesis / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Binding sites / Cancer / Cell Proliferation / Chemistry / Drug Design / Drug Screening Assays, Antitumor / Experiments / Humans / Hydrogen bonds / Kinases / Ligands / MD simulations / MM-GBSA / molecular docking / Molecular Docking Simulation / Molecular Structure / Niacinamide - chemistry / Niacinamide - pharmacology / nicotinamide / PLIP / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - pharmacology / Proteins / Simulation / Structure-Activity Relationship / Vascular endothelial growth factor / Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors / VEGFR-2 inhibitors