Investigating the Impact of Different Acrylamide (Electrophilic Warhead) on Osimertinib’s Pharmacological Spectrum by Molecular Mechanic and Quantum Mechanic Approach
Harun Patel, Iqrar Ahmad, Harsha Jadhav, Rahul Pawara, Deepak K. Lokwani, Sanjay J. Surana
Abstract
BACKGROUND: Lung cancer has become the prominent cause of the cancer-related deaths globally. More than 80 % of all lung cancers have been diagnosed with Non- Small Cell Lung Cancer (NSCLC). The USFDA approved osimertinib to treat patients with metastatic T790M EGFR NSCLC on a regular basis in March 2017. Recently, C797S mutation to osimertinib has been reported, which indicates the need for structural modification to overcome the problem of mutation. METHODS: In this bioinformatics study, we have evaluated the impact of various acrylamide as an electrophilic warhead on the activity and selectivity of osimertinib. RESULT: Osimertinib analouge 48, 50, 60, 61, 67, 75, 80, 86, 89, 92, 93, 116 and 124 were the most active and selective compounds against T790M EGFR mutants compared to Osimertinib. CONCLUSION: These compounds also showed less inclination towards WT-EGFR.