Descriptor-and fragment-based QSAR models for a series of Schistosoma mansoni purine nucleoside inhibitors

The enzyme purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive molecular target for the treatment of major parasitic infectious diseases, with special emphasis on its role in the discovery of new drugs against schistosomiasis, a tropical disease that affects millions of people worldwide. In the present work, we have determined the inhibitory potency and developed descriptor- and fragment-based quantitative structure-activity relationships (QSAR) for a series of 9-deazaguanine analogs as inhibitors of SmPNP. Significant statistical parameters (descriptor-based model: r² = 0.79, q² = 0.62, r²pred = 0.52; and fragment-based model: r² = 0.95, q² = 0.81, r²pred = 0.80) were obtained, indicating the potential of the models for untested compounds. The fragment-based model was then used to predict the inhibitory potency of a test set of compounds, and the predicted values are in good agreement with the experimental resultsA enzima purina nucleosídeo fosforilase de Schistosoma mansoni (SmPNP) é um alvo molecular atrativo para o tratamento de importantes doenças infecciosas parasitárias, com especial ênfase para o seu papel na descoberta de novos fármacos contra a esquistossomose, uma doença tropical que afeta cerca de 200 milhões de pessoas em 74 áreas endêmicas no mundo todo. No presente trabalho, a potência inibitória foi determinada e estudos das relações quantitativas entre a estrutura e atividade (QSAR), baseados em descritores e fragmentos, foram desenvolvidos para uma série de 9-deazaguaninas que atuam como inibidores da SmPNP. Parâmetros estatísticos significantes (modelo baseado em descritor: r² = 0,79; q² = 0,62, r²pred = 0,52; e modelo baseado em fragmento: r² = 0,95; q² = 0,81; r²pred = 0,80) foram obtidos, indicando o potencial dos modelos para compostos ainda não testados. O modelo baseado em fragmento foi então usado para predizer a potência inibitória de um conjunto teste de compostos, e os valores preditos estão em boa concordância com os resultados experimentais.Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB)(FAPESP) São Paulo Research Foundation(CNPq) National Council for Scientific and Technological Developmen

Enzyme kinetics, structural analysis and molecular modeling studies on a series of Schistosoma mansoni PNP inhibitors

The enzyme purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive molecular target for the development of novel drugs against schistosomiasis, a neglected tropical disease that affects about 200 million people worldwide. In the present work, enzyme kinetic studies were carried out in order to determine the potency and mechanism of inhibition of a series of SmPNP inhibitors. In addition to the biochemical investigations, crystallographic and molecular modeling studies revealed important molecular features for binding affinity towards the target enzyme, leading to the development of structure-activity relationships (SAR).A enzima purina nucleosídeo fosforilase do parasita Schistosoma mansoni (SmPNP) é um alvo molecular atrativo para o desenvolvimento de candidatos a novos fármacos para o tratamento da esquistossomose, doença tropical negligenciada que afeta mais de 200 milhões de pessoas em todo mundo. No presente trabalho, estudos de cinética enzimática foram conduzidos para a determinação da potência e do mecanismo de inibição de uma série de inibidores da enzima SmPNP. Além das investigações bioquímicas, estudos cristalográficos e de modelagem molecular revelaram importantes bases moleculares para a afinidade de ligação frente à enzima alvo, levando ao desenvolvimento de relações entre a estrutura e atividade (SAR).(FAPESP) São Paulo Research FoundationFundação de Amparo à Pesquisa do Estado da Bahia (FAPESB)(CNPq) National Council for Scientific and Technological Developmen

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

Selectivity plays a crucial role in the design of enzyme inhibitors as novel antiparasitic agents, particularly in cases where the target enzyme is also present in the human host. Purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive target for the discovery of potential antischistosomal agents. In the present work, kinetic studies were carried out in order to determine the inhibitory potency, mode of action and enzyme selectivity of a series of inhibitors of SmPNP. In addition, crystallographic studies provided important structural insights for rational inhibitor design, revealing consistent structural differences in the binding mode of the inhibitors in the active sites of the SmPNP and human PNP (HsPNP) structures. The molecular information gathered in this work should be useful for future medicinal chemistry efforts in the design of new inhibitors of SmPNP having increased affinity and selectivity. (C) 2010 Elsevier Ltd. All rights reserved.FAPESP (The State of Sao Paulo Research Foundation)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESB (The State of Bahia Research Foundation)Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq (The National Council for Scientific and Technological Development), Brazi

Discovery of New Inhibitors of Schistosoma mansoni PNP by Pharmacophore-Based Virtual Screening

Schistosomiasis is considered the second most important tropical parasitic disease, with severe socioeconomic consequences for millions of people worldwide. Schistosoma monsoni, one of the causative agents of human schistosomiasis, is unable to synthesize purine nucleotides de novo, which makes the enzymes of the purine salvage pathway important targets for antischistosomal drug development. In the present work, we describe the development of a pharmacophore model for ligands of S. mansoni purine nucleoside phosphorylase (SmPNP) as well as a pharmacophore-based virtual screening approach, which resulted in the identification of three thioxothiazolidinones (1-3) with substantial in vitro inhibitory activity against SmPNP. Synthesis, biochemical evaluation, and structure activity relationship investigations led to the successful development of a small set of thioxothiazolidinone derivatives harboring a novel chemical scaffold as new competitive inhibitors of SmPNP at the low-micromolar range. Seven compounds were identified with IC(50) values below 100 mu M. The most potent inhibitors 7, 10, and 17 with 1050 of 2, 18, and 38 mu M, respectively, could represent new potential lead compounds for further development of the therapy of schistosomiasis.FAPESP (The State of Sao Paulo Research Foundation)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)CNPq (The National Council for Scientific and Technological Development), BrazilConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq