Structural and electronic properties of tyrosine kinases inhibitors.

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.

Estudio conformacional, utilizando un potencial atomo-atomo empirico, de aminoacidos biologicamente activos como neurotransmisores. / Conformational study,using an empirical atom-atom potential of biologically active amino acids as neurotransmitters

En la busqueda de una correlacion conformacional que justifique su actividad, se ha estudiado un conjunto de aminoacidos biologicamente activos, y a los cuales se asigna un papel como neurotransmisores: Glutamico, GABA, Aspartico, beta-alanina y taurina. Se estudiaron los zwitter-ion de estos aminoacidos, por ser la especie preponderante a pH fisiologico, empleando como metodo de calculo un potencial atomo-atomo empirico. Como en estudios anteriores, se suposo que la hidratacion eliminaria las interacciones electrostaticas y, consecuentemente, los calculos se realizaron como si las especies no tuvieran cargas. Los resultados obtenidos en las conformaciones de minima energia, en las distancias interatomicas entre grupos presumiblemente activos y en las poblaciones conformacionales, estan en excelente acuerdo con los resultados experimentales de RMN en solucion acuosa