title: Structural and electronic properties of tyrosine kinases inhibitors.
abstract: Protein tyrosine kinases (TKs) regulate cell proliferation, cell differentiation, and play a fundamental role in signal transduction pathway. Uncontrolled signaling from receptor tyrosine kinases and intracellular tyrosine kinases was related to diseases such as cancer, atherosclerosis and psoriasis. For the present study, we selected a number of structurally related ATP-binding site inhibitors of EGF-receptors of diverse classes. Molecular properties of competitive inhibitors are key features for the action mechanism of these compounds. We performed a theoretical study at the RHF/6-311G* level of theory, in order to correlate the molecular parameters with the biological inhibitory activities. Species stability as evaluated by ionization potentials as well as the E(HOMO)-E(LUMO) energy gap, is in very good correlation with higher inhibitory potency (IP). The most active species, 1, 5, 6,10,11 and 12 exhibited strongly negative charged atoms over the C6 and C7 positions, the higher IP, higher mu and higher energy gap. In summary, a good correlation was observed between the molecular parameters, such as ionization potential, dipolar moment and E(HOMO)-E(LUMO) energy gap and inhibitory potency, suggesting that these properties play an important role for the interaction at the ATP-binding site of EGF-receptors.
authors.affiliation: Departamento de Química, Facultad de Quimica, Bioquímica y Farmacia, Universidad Nacional de San Luis, Ejército de los Andes 950, 5700 San Luis, Argentina. msanti@unsl.edu.ar
authors.forename: M B
authors.initials: MB
authors.lastname: Santillán
authors.forename: F
authors.initials: F
authors.lastname: Tomás-Vert
authors.forename: J M
authors.initials: JM
authors.lastname: Aulló
authors.forename: E A
authors.initials: EA
authors.lastname: Jáuregui
authors.forename: G M
authors.initials: GM
authors.lastname: Ciuffo
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry; D011799:Quinazolines / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases