A New Anticancer Semisynthetic Theobromine Derivative Targeting EGFR Protein: CADDD Study.

A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is a (para-chloro)acetamide derivative of the alkaloid, theobromine, (). At first, we started with deep density functional theory (DFT) calculations for to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for . Secondly, the affinity of to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFR and EGFR, Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of have been investigated and its safety and the general drug-likeness predicted. Accordingly, was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly, inhibited in vitro EGFR with an IC value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally, inhibited the growth of A549 and HCT-116 malignant cell lines with IC values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC values of 6.73 and 16.35 µM, respectively.