Rational design-aided discovery of novel 1,2,4-oxadiazole derivatives as potential EGFR inhibitors
| Autor: | Vishal Unadkat, Sanjay Singh, Shishir Rohit, Paranjay Parikh, Vinod Sanna |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Cell Survival In silico hERG Oxadiazole Antineoplastic Agents Biochemistry Polar surface area chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Tumor Cells Cultured Humans Cytotoxicity Molecular Biology Protein Kinase Inhibitors EGFR inhibitors Cell Proliferation Oxadiazoles biology Dose-Response Relationship Drug Molecular Structure Organic Chemistry Rational design Combinatorial chemistry ErbB Receptors chemistry Drug Design biology.protein Lipinski's rule of five Drug Screening Assays Antitumor |
| Zdroj: | Bioorganic chemistry. 114 |
| ISSN: | 1090-2120 |
| Popis: | A molecular dynamics-based sampling of epidermal growth factor receptor tyrosine kinase (EGFR-TK) was carried out to search for energetically more stable protein, which was then used for molecular docking of a series of 1,2,4-oxadiazole derivatives previously reported from our laboratory. A total of 14 compounds were docked, where compounds 6a and 6b showed better binding to EGFR in silico. Further, physicochemical properties of all the compounds were calculated, which suggested that all the molecules obeyed Lipinski’s rule of 5 and had favorable polar surface area and CaCO2 permeability along with the low potential for HERG inhibition. All the compounds were then screened for their ability to produce cytotoxicity in four different cell lines overexpressing EGFR (A549, HCT-116, HEPG2, MCF‐7) and one EGFR negative cancer cell line (SW620); at three concentrations: 10, 1, and 0.1 µM. None of the compounds showed activity against SW620, which suggested that the compounds show cytotoxicity through inhibition of EGFR. Compounds that showed promise in this 3-concentration screen were further subjected to multiple dose–response curves to identify the IC50 values for the shortlisted eight compounds. It was encouraging to see 6a and 6b showing the best IC50 values against almost all the cell-lines which further suggests that our design protocol can be applied to optimize this lead (which are currently in the low micromolar range) to design the homologous compounds to achieve the desired potency in the nanomolar range and also to achieve selectivity across a range of kinases. |
| Databáze: | OpenAIRE |
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