Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-MET

Bioorganic Chemistry
Pankaj Kumar Singh, O Silakari

Abstract

Secondary acquired mutation in EGFR, i.e. EGFR T790M and amplification of c-MET form the two key components of resistant NSCLC. Thus, previously published pharmacophore models of EGFR T790M and c-MET were utilized to screen an in-house database. On the basis of fitness score, indole-pyrimidine scaffold was selected for further evaluation. Derivatives of indole-pyrimidine scaffold with variedly substituted aryl substitutions were sketched and then docked in both the targets. These docked complexes were then subjected to molecular dynamic simulations, to study the stability of the complexes and evaluate orientations of the designed molecules in the catalytic domain of the selected kinases. Afterwards, the complexes were subjected to MM-GBSA calculation, to study the effect of substitutions on binding affinity of double mutant EGFR towards these small molecules. Finally, the designed molecules were synthesized and evaluated for their inhibitory potential against both the kinases using in vitro experiments. Additionally, the compounds were also evaluated against EGFR (L858R) to determine their selectivity towards double mutant, resistant kinase [EGFR (T790M)]. Compound 7a and 7c were found to be possess nanomolar range inhibitory (...Continue Reading

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Citations

Feb 26, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Emmanuel BressoBernard Maigret
Mar 20, 2020·Future Medicinal Chemistry·Shelly Pathania, Ravindra K Rawal
Jun 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Qian ZhangWufu Zhu

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