Computational modelling and analysis of Pyrimidine analogues as EGFR inhibitor in search of anticancer agents

Introduction and Aim:Epidermal Growth Factor Receptor tyrosine kinase is a well-known and widely studied cancer therapeutic target protein. Based on the reported anticancer activity of pyrimidines, a series of 13 compounds are designed. In the present studythe EGFR kinase domain is targeted with the designed 13 compounds. Materials and Methods:With missing residue in the kinase domain of EGFR crystallized structure, the domain is modelled using homology modelling, evaluated, energy-based optimization is carried out using OPLS in Gromacs. The default bindingsite was considered from the known EGFR kinase domain – Erlotinibcomplex crystallized structure. The molecular docking is carried out using AutodockVina, Insilico toxicity profiling and enrichment analysis of pathway is studied using Swiss-ADME and Enrich R.   Results:Compounds 7, 9, 10 and 12 revealed a binding energy of -8.8, -8.3, -8.3 and -8.4 Kcal/mol and makes two h-bonds with MET-769. All the 13 compounds are under the range of Lipnski drug likeness, with high GI-absorption rate. Considering the metabolic enzyme activity, the entire series of compounds are predicted to inhibit the metabolizing enzyme CYP1A2, CYP2D6 and CYP3A4. Compounds 2, 3, 7, 8 and 13 acts as a substrate to CYP2C19 and compound 1, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 act as a substrate to CYP2C9. Conclusion:The inhibition of metabolizing enzyme may affect the poor metabolizing and slowing down the excretion time of molecules from the body. The current in-silico molecular docking, in-silico PKPD study of compounds suggesting that they can be developed as putative lead compounds for developing new anti-cancer drugs.