RESUMEN
A number of triphenylmethane derivatives have been screened against 6-phosphogluconate dehydrogenase from Trypanosoma brucei and sheep liver. Some of these compounds show good inhibition of the enzymes and also selectivity towards the parasite enzyme. Modelling was undertaken to dock the compounds into the active sites of both enzymes. Using a combination of DOCK 3.5 and FLEXIDOCK a correlation was obtained between docking score and both activity for the enzymes and selectivity. Visualisation of the docked structures of the inhibitors in the active sites of the enzymes yielded a possible explanation of the selectivity for the parasite enzyme.
Asunto(s)
Fosfogluconato Deshidrogenasa/antagonistas & inhibidores , Trypanosoma brucei brucei/enzimología , Secuencia de Aminoácidos , Animales , Dominio Catalítico , Simulación por Computador , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Cinética , Modelos Moleculares , Fosfogluconato Deshidrogenasa/química , Programas InformáticosRESUMEN
This paper describes molecular dynamics simulations of prion protein at 300 and 500 K. This was undertaken to gain insight into the factors involved in the stability of prion protein. Simulations were done using the Particle Mesh Ewald (PME) method using a homology model of the C-terminal fragment of human prion protein and the NMR structure of the human prion protein. The simulations at both 300 and 500 K were stable. Simulations were also undertaken with a mutant known to be associated with prion disease: Asp178Asn. The Asp178Asn simulation trajectory was observed to be much less stable than for the wild-type protein trajectory. Significant breakdown in secondary structure was observed for Asp178Asn at 500 K.
Asunto(s)
Priones/química , Priones/genética , Simulación por Computador , Estabilidad de Medicamentos , Humanos , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Mutación Puntual , Estructura Secundaria de Proteína , Electricidad Estática , Temperatura , TermodinámicaRESUMEN
A QSAR study, involving the use of calculated physical properties (TSAR), and the use of a neural network approach (TSAR), has been performed concerning the anti-HIV activity and cytotoxic effects of a series of d4T phosphoramidate derivatives with varying L-alanine esters. Models were obtained which allow reliable predictions for the anti-HIV activity, and cytotoxicity, of these derivatives.