Molecular Docking, Pharmacokinetic and Molecular Simulation Analysis of Novel Mono‐Carbonyl Curcumin Analogs as L858R/T790M/C797S Mutant EGFR Inhibitors

Abstract Introduction : Curcumin, an anticancer natural compound with multiple pharmacological activities, has a weak pharmacokinetic and instability due to diketone moiety. Curcumin's stability challenges can be overcome by removing the diketone moiety and shortening the 7‐carbon chain, resulting in mono‐carbonyl analogs. Cancer proliferation is caused by the activation of Epidermal Growth Factor (EGFR) pathways. Current available EGFR inhibitors have an issue of resistance. Aim : Thus, we aimed to design new mono‐carbonyl curcumin derivatives and analyse their drug likeness properties. Further, to investigate them on three distinct crystal structures, namely two wild‐type and L858R/T790M/C797S mutant generations for EGFR inhibitory activity. Method : Ten New Molecular Entities (NME's) were designed using literature survey. These molecules were subjected to comparative molecular docking, on the EGFR crystal structures viz. wild‐type (PDB: 1M17 and 4I23) and L858R/T790M/C797S mutant (PDB: 6LUD) using Schrodinger software. The molecules were also tested for Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties. The docked complex of the hit molecule was studied for molecular simulation. Result and Discussion : In molecular docking studies, NMEs 1, 2, and 3 were found to have good binding affinity with 1 st , 2 nd , and 3 rd generation EGFR crystal structures and a greater dock score than standard curcumin. All molecules have shown a good ADMET profile. Since L858R/T790M/C797S is currently being explored more, we decided to take the best molecule, NME 3, for molecular dynamics with 6LUD, and the results were compared with those of the co‐crystallized ligand S4 (Osimertinib). It was found that the Relative mean square standard deviation (RMSD) (1.8 Å), Relative mean standard Fluctuation (RMSF) (1.45 Å) and radius of gyration (4.87 Å) values of NME 3 were much lower than those of reference S4. All these confirm that our designed NME 3 is more stable than reference S4. Conclusion : NME 1 and NME 2 have shown better binding against wild type of EGFR. NME 3 have shown comparable binding and more stability as compared to Osimertinib against L858R/T790M/C797S mutated protein structure. The hit compound can be further explored for its Molecular mechanics with generalised Born and surface area solvation (MM‐GBSA) and discrete Fourier transform (DFT) studies to find out the energy and atomic level study. In the future, this molecule could be taken for wet lab studies and can be tested for mutated EGFR inhibitory activity.