Epidermal growth factor receptor mutant T790M-L858R-V948R inhibitor from Calophyllum inophyllum L. leaf as potential non-small cell lung cancer drugs

Abstract

Context: Non-Small Cell Lung Cancer (NSCLC) is the most common lung cancer type, with 80-85% prevalence. Usually, NSCLC is treated by chemotherapy and radiotherapy in collaboration with gefitinib or other anticancer drugs. Those treatments have many adverse effects, such as shortness of breath, bleeding, fever, hair loss, and radiation pneumonitis. Lack of treatment options and numerous mutations greatly contribute to lung cancer's shocking death toll. Therefore, potential EGFR mutant inhibitors need to be analyzed. Aims: To identify potential inhibitors of an epidermal growth factor receptor (EGFR) mutant derived from Calophyllum inophyllum L. leaf using an in silico approach. Methods: In silico analysis and literature study were carried out. Secondary metabolite compounds from C. inophyllum were obtained through the PubChem database, and their biological activity and ADMET were analyzed. Molecular docking with EGFR wild-type (5FED) and mutant (5HG7) was carried out using PyRx. Furthermore, amino acid residues were analyzed using Discovery Studio. Results: Based on overall screening and molecular docking, a non-toxic compound with a low binding affinity with EGFR mutant protein is 4-[2-(4-nitrophenyl)ethylcarbamoyl]benzenesulfonyl. Moreover, interactions and hydrogen bonds at Ala743, Gly796, Leu718, Phe856, Leu844, and Val726 are known to play a crucial role in ATP binding inhibition toward the tyrosine kinase domain, resulting in EGFR mutant inhibition. Conclusions: 4-[2-(4-nitrophenyl)ethylcarbamoyl]benzenesulfonyl is one of the potential candidates as an EGFR mutant protein by ATP binding inhibition. However, in vitro and in vivo research needs to be performed to confirm these results.