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

Abstract

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).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).

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

“…As expected based on previous studies, 10,17 Although structure-activity relationships (SAR) have been widely described in the last decades for groundstate mammalian PNP inhibitors, the opposite situation is true for SmPNP inhibitors. It was only more recently that the first SAR studies were provided in the literature, describing key structural requirements for SmPNP affinity and selectivity.…”

“…It was only more recently that the first SAR studies were provided in the literature, describing key structural requirements for SmPNP affinity and selectivity. 10,17 These studies suggest that hydrophobic interactions in the active site of SmPNP play an important role in the binding affinity of the inhibitors. In spite of their significance and usefulness, the SAR information, of qualitative nature, would gain strategic advantages in drug design through the incorporation of statistical predictive modeling capabilities.…”

“…On one hand, it has been proposed that compounds possessing aryl groups in the 9 position of the purine ring (such as 15 and 26) can reach the hydrophobic pocket in the vicinity of Phe161. 17 On the other hand, 9-substituted compounds with shorter and non-planar chains can bind loosely, being easily displaced by water molecules. Taken together, these evidences clarify the opposite role of the fragments of compound 14 in the H-bonding to Asn245 and Glu203 (reddish colored, poor H-bonding capability) in comparison with the corresponding fragments in compounds 15 and 26 (colored in green, stronger H-bonding network).…”

Structure- and ligand-based drug design approaches for neglected tropical diseases

“…An example can be seen in the medicinal chemistry approach employed for the discovery of new inhibitors of Schistosoma mansoni purine nucleoside phosphorylase (SmPNP), which outlines a successful scenario for the integration of computational and experimental methods. PNP is a key enzyme involved in the purine salvage pathway of S. mansoni, one of the causative agents of human schistosomiasis [53,54]. In this work, a structure-based pharmacophore model was employed for the virtual screening of a huge library of compounds, leading to the identification of three thioxothiazolidinones derivatives with substantial in vitro inhibitory activity against SmPNP (Fig.…”

The molecular structure of Schistosoma mansoni PNP isoform 2 provides insights into the nucleotide selectivity of PNPs

“…The structure and functional properties of the S. mansoni purine nucleoside phosphorylase isoform 1 (SmPNP1) were reported by our group previously (16)(17)(18)(19)(20)(21)(22)(23)(24). The enzyme uses inosine and guanosine as substrates as it has been determined that the main determinant specificity of LMM PNPs towards 6-oxopurines is due to the presence of asparagine in the active site (N243 in human and N245 in S. mansoni PNPs).…”