title: Inhibitory activity against epidermal growth factor receptor (EGFR) based on single point mutations of active site residues.
abstract: Epidermal growth factor receptors belong to the ErbB family of receptor tyrosine kinases (TKs) involved in the proliferation of normal and malignant cells. EGFR has attracted considerable attention as a target for cancer therapy. The findings reported herein are believed to provide some novel insights into the design of effective drugs for the therapeutic treatment of EGFR-related cancers. In particular, it is shown using sophisticated computational tools in a systematic way that the affinity of a wide spectrum of thiazolo[4,5-d]pyrimidine analogs can be carefully tuned up by seeking the desired goal in the structural modifications of EGFR, such as single point mutations of the critical EGFR residues in the active site. It is also demonstrated that a large number of the small ligand molecules can be efficiently divided into subgroups of the structurally similar ligands and that every such a subgroup has its unique inhibitory activity signature. The protein engineering approach, as quite reproducible, is proposed to be a viable partner to experiment in addressing a variety of issues, including investigation of clinically important mutations, development of drug resistance, identification of the most promising anti-cancer drug candidates, etc.
authors.affiliation: Department of Material Science and Chemistry, Faculty of Systems Engineering, Wakayama University, 930 Sakaedani, Wakayama, 640-8510 Japan and Belgrade Institute of Science and Technology, 11060 Belgrade, Serbia. petar.mitrasinovic@yahoo.com.
authors.forename: Petar M
authors.initials: PM
authors.lastname: Mitrasinovic
mesh_terms: D020134:Catalytic Domain / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000077341:Lapatinib; D015394:Molecular Structure; D017354:Point Mutation / Q000235:genetics*; D015202:Protein Engineering; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D013844:Thiazoles; D000077341:Lapatinib; D066246:ErbB Receptors