Rational design-aided discovery of novel 1,2,4-oxadiazole derivatives as potential EGFR inhibitors

• Published in: Bioorganic chemistry Vol. 114; p. 105124
• Main Authors: Unadkat, Vishal, Rohit, Shishir, Parikh, Paranjay, Sanna, Vinod, Singh, Sanjay
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2021
• Subjects: 4-oxadiazole; Anti-cancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; EGFR; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Humans; Models, Molecular; Molecular docking; Molecular dynamics; Molecular Structure; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship; Tumor Cells, Cultured; 1; 2; 4-oxadiazole; Molecular dynamics; Anti-cancer; EGFR; Molecular docking
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105124

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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.