Design of inhibitors for nucleoside hydrolase from Leishmania donovani using molecular dynamics studies

Abstract

Neste trabalho é proposto o primeiro modelo por homologia para a nucleosídeo hidrolase de Leishmania donovani construído a partir das estruturas das nucleosídeo hidrolases de Crithidia fasciculata e de Leishmania major. Usando as informações de interação entre o inibidor p-aminofeniliminoribitol e a nucleosídeo hidrolase de Crithidia fasciculata foram planejados dois novos potenciais inibidores, os quais apresentam novas interações com alguns resíduos da bolsa hidrofóbica do sítio ativo do modelo. Simulações por dinâmica molecular dos protótipos ancorados nos sítios ativos do modelo e das enzimas usadas como moldes, mostraram que, diferente do p-aminofeniliminoribitol, eles permaneceram ancorados nos sítios ativos das três enzimas ao longo de toda a dinâmica, interagindo fortemente com os aminoácidos da bolsa hidrofóbica.In this work we propose the first homology model for nucleoside hydrolase from Leishmania donovani, built based on the crystallographic structures of Crithidia fasciculata and Leishmania major nucleoside hydrolases. We used the interaction information from the crystallographic model of the enzyme of C. fasciculata in complex with the inhibitor p-aminophenyliminoribitol, to design two new potential inhibitors, which present new interactions with some residues of the hydrophobic pocket of the model active site. Molecular dynamics simulations of the prototypes inside the active sites of the model and the template enzymes showed that, differently from p-aminophenyliminoribitol, they remained tightly bound inside the active sites, interacting strongly with the amino acids from the hydrophobic pocket. Keywords: visceral leishmaniasis, Leishmania donovani, metalloproteins, homology modeling, molecular dynamics IntroductionAccording to the World Health Organization (WHO), leishmaniasis is a threat for 350 million people in 88 countries, where 72 of those are developing countries. WHO also estimates that 12 million people in the world are infected and 2 million new cases appear annually, despite the official report of only about 600,000 new cases every year. 1 It is clear that leishmaniasis is one of the most important parasitic diseases, which is caused by protozoan of the Leishmania genus. This disease affects humans in four different forms with a broad range of clinical manifestations: visceral, mucocutaneous, cutaneous and diffuse cutaneous leishmaniasis. [1][2][3][4] Visceral leishmaniasis, also known as "kala-azar", is considered the most dangerous form of this disease, being fatal in 100% of the untreated cases 1 and is caused by the L. donovani complex. 4The search for prevention against leishmaniasis infection includes vaccines with weakened and genetically modified strains of the parasite and recombinant antigens 5 or its encoding DNA. 6 The only preventive treatment for leishmaniasis available today is the canine vaccine 65 França et al. Vol. 19, No. 1, 2008 Leishmune ® . 7 An efficient human vaccine is not available yet. Accordingly, the most effective way to combat leishmaniasis stil...

Aspectos Moleculares Associados À Cardiomiopatia Chagásica E À Reativação Da Infecção Em Pacientes Cardiopatas Transplantados

“…são parte de uma superfamília de metalo-proteínas relacionadas estruturalmente, com uma topologia original de cadeias β (FRANÇA et al 2008). Todas as NH estudadas estão na forma de homodímeros ou homotetrâmeros (Figura 2) e apresentam grande similaridade na sequência de aminoácidos do sítio ativo, indicando que elas estão intimamente relacionadas estruturalmente e no mecanismo catalítico (SHI et al 1999).…”

Hydrolytic Glycosidic Bond Cleavage in RNA Nucleosides: Effects of the 2′-Hydroxy Group and Acid–Base Catalysis

“…Despite detailed studies on DNA deglycosylation, little is known about the corresponding reaction in RNA. Although computational work has considered select aspects of specific enzyme-catalyzed reactions, ,− such studies do not reveal the intrinsic stability of the glycosidic bond in RNA or comprehensively isolate ways the associated barrier can be reduced across all natural RNA nucleosides. Thus, while enzymes such as RNA glycosidases and nucleoside hydrolases may use at least some of the catalytic strategies outlined above to facilitate deglycosylation, the individual contributions of each approach are currently unclear.…”