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

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.