Synthesis, docking, 4D-QSAR and dynamics simulation of sorbamide derivatives as EGFR inhibitors

The epidermal growth factor receptor (EGFR), a validated therapeutic target in oncology, demonstrates overexpression across multiple neoplastic cell types and plays a critical role in tumorigenesis. This investigation reports the strategic synthesis and evaluation of antiproliferative efficacy for novel sorbamide derivatives designed as EGFR inhibitors. Several synthesized compounds exhibited moderate inhibitory effects against EGFR-overexpressed A431 carcinoma cells, and among them, compound 7d demonstrated superior potency relative to the reference agent Gefitinib with an IC₅₀ value of 19.1 µM. A predictive 4D-QSAR model was successfully developed, exhibiting satisfactory statistical parameters (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi>r</mml:mi><mml:mrow><mml:mi>t</mml:mi><mml:mi>r</mml:mi></mml:mrow><mml:mn>2</mml:mn></mml:msubsup></mml:math> = 0.81, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi>Q</mml:mi><mml:mrow><mml:mi>L</mml:mi><mml:mi>O</mml:mi><mml:mi>O</mml:mi></mml:mrow><mml:mn>2</mml:mn></mml:msubsup></mml:math> = 0.62, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi>Q</mml:mi><mml:mrow><mml:mi>L</mml:mi><mml:mi>M</mml:mi><mml:mi>O</mml:mi></mml:mrow><mml:mn>2</mml:mn></mml:msubsup></mml:math> = 0.60, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi>r</mml:mi><mml:mrow><mml:mi>Pred</mml:mi></mml:mrow><mml:mn>2</mml:mn></mml:msubsup></mml:math> = 0.71). Complementary computational analyses through covalent docking and molecular dynamics simulations elucidated the molecular interaction mechanism, revealing covalent bond formation between the sorbamide scaffold and the conserved Cys797 residue in the EGFR catalytic domain.