Computational and Metabolic Studies on a Set of N-Myristoyltransferase Inhibitors Against Trypanosoma Brucei

Computational and Metabolic Studies on a Set of N-Myristoyltransferase Inhibitors Against Trypanosoma Brucei

Luciana Scotti (Federal University of Paraíba, João Pessoa, Brazil), Hamilton Ishiki (University of Oeste Paulista, Presidente Prudente, Brazil), Francisco Jaime Bezerra Mendonça Junior (Biological Science Department, Laboratory of Synthesis and Drug Delivery, State University of Paraiba, João Pessoa, Brazil), Frederico Fávaro Ribeiro (Federal University of Pernambuco, Recife, Brazil), Nagendra Sastry Yarla (Institute of Science, GITAM University, Visakhapatnam, India), Marcelo Sobral da Silva (Federal University of Paraíba, João Pessoa, Brazil), José Maria Barbosa Filho (Federal University of Paraíba, João Pessoa, Brazil) and Marcus Tullius Scotti (Federal University of Paraíba, João Pessoa, Brazil)
DOI: 10.4018/IJQSPR.2018070106

Abstract

This article describes how the Human African trypanosomiasis (HAT) is a neglected disease caused by Trypanosoma brucei. Only four drugs are available for treating HAT. Despite years of effort, little progress has been made in identifying orally available chemotypes active against the parasite. In this study, chemometric tools, such as, Principal Component Analysis (PCA) and Partial Least Squares Regression (PLS), were applied to a set of active trypanocidal N-Myristoyltransferase inhibitors. These tools were generated using the Pentacle software. The algorithm (AMANDA), the descriptors are calculated through the molecular interaction fields with the blocks: N1, O, TIP and N1, which allow extracting from them the most interesting regions. The PCA selected 507 descriptors and the scores plot clearly separated more active compounds from others. The first two PCs account for over 70% of data variance. The best PLS model, exhibits q2 = 0.762 and r2 = 0.867 and rext2 = 0.69. The results highlight the importance of acceptor hydrogen bonds regions. The importance of the metabolic cleavage of the methyl group attached to the nitrogen of pyrrole ring by N-dealkylation was observed.
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Introduction

Sleeping sickness or human African trypanosomiasis (HAT) is perhaps the most neglected disease that exists because it is restricted to the African continent, reaching the poorest population between 15 and 45 years inhabitants of rural areas who work in agriculture or fishing (OMS, 2005; Steverding, 2010; CDC, 2013). According to the World Health Organization, between 300,000 and 500,000 people are infected, 60 million are threatened and sleeping sickness is responsible for 15,000 to 30,000 deaths annually. After the bite of the vector tsetse flies (Glossina spp.), the Trypanosoma brucei (T. brucei) remains in the bloodstream, and there is a period that can last for weeks asymptomatic subsequently begin to emerge the acute framework (stage 1) with frequent fevers, fatigue, vomiting (WHO, 2013). Then the T. brucei reaches the central nervous system (stage 2), causing great dependency, to lead the host to death (Balasegaram et al., 2006; Patterson et al., 2011; WHO, 2013).

Although there are therapies available for the treatment of HAT, most drugs are associated with severe side effects or are complicated to administer. New drugs are urgently needed. The enzyme N-myristoyltransferase (NMT) is an interesting target because it is different to the mammalians and it is related to the survival of the parasite by RNA interference (Price et al., 2010; Boutin, 1997). NMT catalyzes the co-translational transfer of myristate from myristoyl-CoA to the N-terminal glycine, a constituent of proteins and influencing the functioning of cell membranes (see Figure 1). The myristate group is then transferred in a nucleophilic addition−elimination reaction, which is followed by sequential release of CoA followed by the myristoylated protein (Rajala et al., 2000). Myristate is also a component of the glycophosphatidylinositol (GPI) lipid anchors that tether the major classes of surface molecules in trypanosomatid parasites (Price et al., 2003).

Figure 1.

Catalytic activity of the N-myristoyl-transferase

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