RESUMO
There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure-activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24-48 h before PfDHODH inhibition would be expected to do so.
Assuntos
Antimaláricos/química , Inibidores Enzimáticos/química , Malária Falciparum/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Quinolonas/química , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Di-Hidro-Orotato Desidrogenase , Desenho de Fármacos , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Quinolonas/efeitos adversos , Quinolonas/farmacocinéticaRESUMO
There is currently a great deal of interest in creating computational tools for predicting the pharmacological properties of drug development candidates, ranging from physicochemical properties such as pK(a) and solubility to more complex biological properties such as oral bioavailability and toxicity. The limiting factor in many cases is a shortage of good data from which to construct training sets. In other cases, large amounts of data are available, but they use surrogate end-points or are comprised of compounds very different from those usually encountered in drug discovery and development. In such cases large training sets and global models are not necessarily better than local models based on smaller data sets. Such considerations make it as important to examine the available data carefully so as to avoid over-interpretation of the models obtained as it is to minimise errors in prediction per se. The kinds of complications likely to be encountered for in vitro hepatotoxicity modelling are discussed in general terms and illustrated in particular by SIMCA analysis of data obtained from assays of cultured hepatocytes for a large, structurally diverse data set and a smaller, much more focussed one.