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

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 (()-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound , 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 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 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 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of -(4-(hydrazinecarbonyl)phenyl)benzamide with -(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group.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 prohibited VEGFR-2 with an IC value of 51 nM. Compound also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC values of 8.25 and 6.48 μM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively.