Dataset Information

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

ABSTRACT: 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of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group.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.

SUBMITTER: Elkaeed EB

PROVIDER: S-EPMC9317904 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Elkaeed Eslam B EB Yousef Reda G RG Elkady Hazem H Gobaara Ibraheem M M IMM Alsfouk Bshra A BA Husein Dalal Z DZ Ibrahim Ibrahim M IM Metwaly Ahmed M AM Eissa Ibrahim H IH

Molecules (Basel, Switzerland) 20220719 14

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 w ...[more]

PMID: 35889478

Similar Datasets

Project description:In this work, new thieno[2,3-d]pyrimidine-derived compounds possessing potential anticancer activities were designed and synthesized to target VEGFR-2. The thieno[2,3-d]pyrimidine derivatives were tested in vitro for their abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two types of cancer cells, MCF-7 and HepG2. Compound 18 exhibited the strongest anti-VEGFR-2 potential with an IC50 value of 0.084 μM. Additionally, it displayed excellent proliferative effects against MCF-7 and HepG2 cancer cell lines, with IC50 values of 10.17 μM and 24.47 μM, respectively. Further studies revealed that compound 18 induced cell cycle arrest in G2/M phase and promoted apoptosis in MCF-7 cancer cells. Apoptosis was stimulated by compound 18 by increasing BAX (3.6-fold) and decreasing Bcl-2 (3.1-fold). Additionally, compound 18 significantly raised the levels of caspase-8 (2.6-fold) and caspase-9 (5.4-fold). Computational techniques were also used to investigate the VEGFR-2-18 complex at a molecular level. Molecular docking and molecular dynamics simulations were performed to assess the structural and energetic features of the complex. The protein-ligand interaction profiler analysis identified the 3D interactions and binding conformation of the VEGFR-2-18 complex. Essential dynamics (ED) study utilizing principal component analysis (PCA) described the protein dynamics of the VEGFR-2-18 complex at various spatial scales. Bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-18 complex. In addition, the DFT studies provided insights into the structural and electronic properties of compound 18. Finally, computational ADMET and toxicity studies were conducted to evaluate the potential of the thieno[2,3-d]pyrimidine derivatives for drug development. The results of the study suggested that compound 18 could be a promising anticancer agent that may provide effective treatment options for cancer patients. Furthermore, the computational techniques used in this research provided valuable insights into the molecular interactions of the VEGFR-2-18 complex, which may guide future drug design efforts. Overall, this study highlights the potential of thieno[2,3-d]pyrimidine derivatives as a new class of anticancer agents and provides a foundation for further research in this area.

Project description:Chronic diseases such as diabetes and cancer are the leading causes of mortality worldwide. Receptors for Advanced Glycation End products (RAGEs) are ubiquitous factors that catalyse Advanced Glycation End products (AGEs), proteins, and lipids that become glycated from sugar ingestion. RAGEs are cell surface receptor proteins and play a broad role in mediating the effects of AGEs on cells, contributing to modifying biological macromolecules like proteins and lipids, which can cause Reactive Oxygen Species (ROS) generation, inflammation, and cancer. We targeted RAGE inhibition analysis and screening of United States Food and Drug Administration (FDA) libraries through molecular docking studies that identified the four most suitable FDA compounds: Zytiga, Paliperidone, Targretin, and Irinotecan. We compared them with the control substrate, Carboxymethyllysine, which showed good binding interaction through hydrogen bonding, hydrophobic interactions, and π-stacking at active site residues of the target protein. Following a 100 ns simulation run, the docked complex revealed that the Root Mean Square Deviation (RMSD) values of two drugs, Irinotecan (1.3 ± 0.2 nm) and Paliperidone (1.2 ± 0.3 nm), were relatively stable. Subsequently, the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) determined that the Paliperidone molecule had a high negative energy of -13.49 kcal/mol, and the Absorption, Distribution, Metabolism, and Excretion (ADME) properties were in control for use in the mentioned cases. We extended this with many in vitro studies, including an immunoblotting assay, which revealed that RAGEs with High Mobility Group Box 1 (HMGB1) showed higher expression, while RAGEs with Paliperidone showed lower expressions. Furthermore, cell proliferation assay and Apoptosis assay (Annexin-V/PI staining) results revealed that Paliperidone was an effective anti-glycation and anti-apoptotic drug-however, more extensive in vivo studies are needed before its use.

Project description:Based on unselectively, several side effects and drug resistance of available anticancer agents, the development and research for novel anticancer agents is necessary. In this study, a new series of quinazoline-4(3H)-one derivatives having a thiol group at position 2 of the quinazoline ring (8a-8 h) were designed and synthesized as potential anticancer agents. The Chemical structures of all compounds were characterized by 1H-NMR, 13C-NMR, and Mass spectroscopy. The antiproliferative activity of all derivatives were determined against two cancer cell lines (MCF-7 and SW480) and one normal cell lines (MRC-5) by the MTT method. Cisplatin, Erlotinib and Doxorubicin were used as positive controls. The results of in vitro screening showed that 8a with an aliphatic linker to SH group was the most potent compound with IC50 values of 15.85 ± 3.32 and 17.85 ± 0.92 µM against MCF-7 and SW480 cell lines, respectively. 8a indicated significantly better potency compared to Erlotinib in the MCF-7 cell line. The cytotoxic results obtained from testing compound 8a on the normal cell line, revealing an IC50 value of 84.20 ± 1.72 µM, provide compelling evidence of its selectivity in distinguishing between tumorigenic and non-tumorigenic cell lines. Structure-activity relationship indicated that the variation in the anticancer activities of quinazoline-4(3H)-one derivatives was affected by different substitutions on the SH position. Molecular docking and MD simulation were carried out for consideration of the binding affinity of compounds against EGFR and EGFR-mutated. The binding energy of compounds 8a and 8c were calculated at -6.7 and - 5.3 kcal.mol- 1, respectively. Compounds 8a and 8c were found to establish hydrogen bonds and some other important interactions with key residue. The DFT analysis was also performed at the B3LYP/6-31 + G(d, p) level for compounds 8a, 8c and Erlotinib. Compound 8a was thermodynamically more stable than 8c. Also, the calculated theoretical and experimental data for the IR spectrum were in agreement. The obtained results delineated that the 8a can be considered an appropriate pharmacophore to develop as an anti-proliferative agent.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets