Virtual screening of Osimertinib and Dacomitinib Analogues with potential activity on EGFR (T790M and l858R Mutations) for non-small cell lung cancer treatment

Abstract

Introduction: Tyrosine kinase inhibitors (TKIs) drugs act on epidermal growth factor (EGFR) receptors to treat Non-small cell lung cancer (NSCLC). However, mutations on EGFR receptors T790M and L858R allow just a global response rate (GRR) of 80% with Osimertinib, while Erlotinib and Gefitinib only 10%. Objective: To identify promising molecules analogues to tyrosine kinase inhibitor (TKIs) drugs with the potential capacity to bind the native and mutated EGFR receptor (T790M and L858R) to avoid mutational resistance in NSCLC. Methods: Virtual screening by molecular docking between analogues of Osimertinib (DB09330) and Dacomitinib (DB11963) drugs retrieved of DRUGBANK database and receptors of native EGFR and mutated on L585R and T790M obtained of Protein Data Bank was performed, using PyRx software. Finally, toxicological prediction was made using GUSAR. Results: Analogues studied, DB03878, DB04739, DB07280 and DB06876 achieved significant affinity (-9,1 y -8,3 Kcal/mol) on mutated T790M EGFR compared with osimertinib (-7,6 Kcal/mol). Similarly, DB08091, DB08730, DB07220 and DB06920 achieved significant affinity (between 9.4 and -8.9 Kcal/mol) on L858R EGFR mutated compared with dacomitinib (-7.0 Kcal/mol). Overall, there were predominance of Van der Waals forces and links π-alkyl. Also, two analogues were safe with category IV according to predictions, DB08730 and DB03878. Conclusions: Eight TKI analogues showed superior binding energy over EGFR compared to reference drugs. According to toxicological predictions only 2 analogues were selected as promising TKI-type safe candidates for the treatment of resistant NSCLC.