A complete model of the Plasmodium falciparum bifunctional enzyme dihydrofolate reductase-thymidylate synthase: a model to design new antimalarials

Abstract

É proposto um modelo teórico para a pfDHFR-TS que inclui os 55 aminoácidos que não foram contemplados no modelo cristalográfico. O cálculo do potencial eletrostático sobre a superfície do modelo, revelou uma região contínua de potencial positivo conectando os dois sítios ativos, sugerindo um mecanismo otimizado de transporte de dihidrofolato.We propose a theoretical model for pfDHFR-TS, which includes the 55 aminoacid residues ignored in the crystallographic model. The electrostatic potential calculation on the model surface revealed a continuous positive potential region between the two active sites, suggesting an optimized mechanism for dihydrofolate transport. Keywords: malaria, homology modeling, DHFR-TS, optimized substrate transport, Plasmodium falciparum IntroductionMalaria is one of the most serious widespread parasitic diseases in humans. Nowadays, at least 300 million people are infected by malaria every year, with something in between 2 and 3 million deaths. To worsen the situation, the population that lives in endemic areas is about 2 billion people or 40% of the world population.1 It is possible that the rise in Earth temperature will eventually increase the endemic areas to include greater extensions of Europe and North America. In some parts of Africa, 10% of the deaths of children less than five years old are due to the direct effects of malaria. In fact, the actual epidemic of malaria makes it impossible to calculate the contribution of this disease to the mortality rate of children of this age due to other sickness. 2 The World Health Organization (WHO) estimates that 3,000 children under 5 years old die of malaria in Africa every day, 3 a situation that Mankind should not tolerate. In addition and frequently overlooked in the case of malaria caused by Plasmodium falciparum, there is considerable morbidity associated with this disease that manifests as chronic severe anemia in children and adults. In Brazil, the most important endemic areas of malaria are situated in Amazonian Region, where this disease is one of the major hindrances to the progress of the region, leading to 300,000 to 400,000 new reported cases every year. 4Malaria is a disease of the poorest regions of the planet, and because of this, the interest of the major pharmaceutical companies in the development of economically feasible chemotherapy is very low or does not exist. In fact, the strategies used against malaria, like chemotherapy and the use of insecticides, are often not accessible to the populations of the endemic areas due to economic and social reasons.One of the major obstacles to the control of malaria is the rapid spread of parasite resistance to the current available chemotherapy and of the mosquito vector to insecticides. This phenomenon has rendered other times wonderful antimalarials, such as chloroquine, completely useless in several regions.5-7 Also, it should be expected that resistance should eventually rise for any new drug that we develop in the future, thus making the search of new antimalarial chemother...

Molecular dynamics of the interaction of Plasmodium falciparum and human serine hydroxymethyltransferase with 5-formyl-6-hydrofolic acid analogues: design of new potential antimalarials

“…A similar hypothesis has already been studied in a previous work where we proposed that a continuous positive potential region between the two active sites of the bifunctional enzyme Dihydrofolate Reductase-Tymidilate Synthase (DHFR-TS) of P. falciparum, could be involved in an optimized mechanism for the transport of dihydrofolate negatively charged from TS active site to DHFR active site. 9 In the present work, the interaction energy of the compounds with the enzymes was estimated using the Insight Discovery 2000 package, 13 and are in complete agreement with this hypothesis. Table 2 presents, for each compound, theoretical values corresponding to the electrostatic and van der Waals contributions to the energy of interaction of hSHMT and pfSHMT with the designed compounds.…”

“…A good strategy already discussed in a former work 8 relies on the development of inhibitors for the enzymes of the parasite methylenetetrahydrofolate cycle using molecular modeling and dynamics studies. [9][10][11][12] Among those enzymes, Plasmodium falciparum Serine Hydroxymethyltransferase (pfSHMT) is the only one that has yet not been seen as a potential target to antimalarials. This probably happens because of the great sequence identity of this enzyme with human Serine Hydroxymethyltransferase (hSHMT), which could implicate in poor selectivity.…”

New approaches in antimalarial drug discovery and development: a review

“…New drugs are designed based on previous leads and the stabilities of the ligands inside the binding pockets are further verified using molecular dynamics simulations. A large variety of new antimalarial candidates has been identified using MM among new and well-established drug targets, such as enzymes involved in the folate cycle (SHMT and DHFR-TS) (França et al 2004, da Silva et al 2010, LDH (Penna-Coutinho et al 2011), enoyl-acyl carrier protein reductase (ENR) (Nicola et al 2007), protein kinases (Keenan et al 2005), cysteine proteases (Shah et al 2011), topoisomerases (Roy et al 2011) and spermidine synthase (SpdSyn) (Jacobsson et al 2008). …”

Malária: aspectos históricos e quimioterapia

“…Esta inibição interfere na habilidade do Plasmodium em converter o ácido dihidrofólico em tetra-hidrofolato, cofator importante no processo de síntese de ácidos nucléicos e aminoácidos. Esta enzima, que teve sua estrutura determinada recentemente por métodos de difração de raios-X, 39 tem sido alvo de diversos estudos por modelagem molecular visando o planejamento de novos antimaláricos [40][41][42][43][44] e, mais recentemente, outra enzima deste ciclo, a serina hidroximetiltransferase (SHMT) também tem sido vista na literatura como potencial alvo para novos antimaláricos, apesar da sua grande semelhança seqüencial e estrutural com a enzima humana. 45,46 Inibidores da DHFR são potentes agentes esquizonticidas que atuam sobre formas assexuadas do parasita.…”