Abstract
Background and objectives: Cancer represents the miscommunication between and within the body cells. The mutations of the oncogenes encoding the MAPK pathways play an important role in the development of tumoral diseases. The mutations of KRAS and BRAF oncogenes are involved in colorectal cancer and melanoma, while the NRAS mutations are associated with melanoma. Thiazolidine-2,4-dione is a versatile scaffold in medicinal chemistry and a useful tool in the development of new antitumoral compounds. The aim of our study was to predict the pharmacokinetic/pharmacodynamic properties, the drug-likeness and lead-likeness of two series of synthetic 5-arylidene(chromenyl-methylene)-thiazolidinediones, the molecular docking on the oncoproteins K-Ras, N-Ras and B-Raf, and to investigate the cytotoxicity of the compounds, in order to select the best structural profile for potential anticancer agents. Materials and Methods: In our paper we studied the cytotoxicity of two series of thiazolidine-2,4-dione derivatives, their ADME-Tox properties and the molecular docking on a mutant protein of K-Ras, two isoforms of N-Ras and an isoform of B-Raf with 16 mutations. Results: The heterocyclic compounds strongly interact with K-Ras and N-Ras right after their posttranslational processing and/or compete with GDP for the nucleotide-binding site of the two GTPases. They are less active against the GDP-bound states of the two targets. All derivatives have a similar binding pattern in the active site of B-Raf. Conclusions: The data obtained encourage the further investigation of the 5-arylidene(chromenyl-methylene)-thiazolidinediones as potential new agents against the oncoproteins K-Ras, N-Ras and B-Raf.
Highlights
Cancers are a group of diseases which can be perceived as miscommunications between the cells and within the cells
Based on our team’s experience in the virtual screening, molecular docking, chemical synthesis and biological investigation of different heterocyclic-based compounds [32,33,34], we present here the investigation of the cytotoxicity of two series of 5-arylidene-thiazolidine-2,4diones, their ADME-Tox profiling and the molecular docking on K-Ras, N-Ras and B-Raf proteins
A series of FAF-Drugs30 s build-in filters for lead-likeness, drug-likeness, detection of non-peptidic inhibitors of protein-protein interactions (PPIs) [39], detection of undesirable moieties and substructures (UMSs) involved in toxicity problems [40,41,42,43,44,45,46,47,48,49,50], covalent inhibitors [51,52], Pan-Assay Interference Compounds (PAINS) [53,54] and a series of customized filters for safety profiling [44,55,56,57] were exploited for the ADME-Tox screening
Summary
Cancers are a group of diseases which can be perceived as miscommunications between the cells and within the cells. Oncogenes are genes that encode proteins able to induce cancer via various metabolic pathways. Somatic mutations in genes encoding the mitogen-activated protein kinase (MAPK). Oncogenic mutations in MAPK signaling pathways frequently. Medicina 2019, 55, 85 affect the Ras proteins and the serine/threonine-protein kinase B-Raf (B-Raf) in the extracellular signal-regulated kinase pathway [1,2,3]. In this respect, the most common somatic mutations of Kirsten. The mutations of the oncogenes encoding the MAPK pathways play an important role in the development of tumoral diseases. Materials and Methods: In our paper we studied the cytotoxicity of two series of thiazolidine-2,4-dione derivatives, their ADME-Tox properties and the molecular docking on a mutant protein of K-Ras, two isoforms of N-Ras and an isoform of
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