In our previous study, a protein engineering approach, accounting for the effects of single point mutations
of the binding site residues on the stability of 22 thiazolo[4,5-d]pyrimidines in complex with the intracellular kinase
domain of EGFR (PDB ID: 1XKK), was established in a systematic manner to be an efficient strategy for
the identification of anti-EGFR-related-cancer drug candidates. The inhibitory activities of two lignad molecules,
4-(7-(3-chloro-4-morpholinophenylamino)thiazolo[4,5-d]pyrimidin-2-ylamino)benzenesulfonamide and 4-(7-(4-morpholinophenylamino)
thiazolo[4,5-d]pyrimidin-2-ylamino)benzenesulfonamide, exhibited some sort of uniqueness. Regardless
of a slight mutual structural difference between these two ligands in only a peripheral Cl atom, their inhibitory activities
against EGFR appeared to be associated with two quite opposite structural bases respectively. Herein, the fundamental rationalization
of the remarkable standpoint is elaborated using both molecular docking and molecular dynamics simulations.
Consequently, a number of implications of vital importance for the successful structure-based design of
prospective drugs against EGFR-related cancers are discussed.