Abstract
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.
Keywords: Cancer, drug design, EGFR, inhibitor, ligand, single point mutation, thiazolo pyrimidine, tyrosine kinase.
Medicinal Chemistry
Title:Structural Elucidation of Unique Inhibitory Activities of Two Thiazolo[ 4,5-d]pyrimidines Against Epidermal Growth Factor Receptor (EGFR): Implications for Successful Drug Design
Volume: 10 Issue: 1
Author(s): Petar M. Mitrasinovic
Affiliation:
Keywords: Cancer, drug design, EGFR, inhibitor, ligand, single point mutation, thiazolo pyrimidine, tyrosine kinase.
Abstract: 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.
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Mitrasinovic M. Petar, Structural Elucidation of Unique Inhibitory Activities of Two Thiazolo[ 4,5-d]pyrimidines Against Epidermal Growth Factor Receptor (EGFR): Implications for Successful Drug Design, Medicinal Chemistry 2014; 10 (1) . https://dx.doi.org/10.2174/157340641001131226122124
DOI https://dx.doi.org/10.2174/157340641001131226122124 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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