N-Myristoyltransferases as antileishmanial targets: a piggyback approach with benzoheterocyclic analogues

Leishmaniasis is one of the neglected diseases that remain in need for pharmacological alternatives. In this context, N-Myristoyltransferases (NMT) arise as interesting targets to explore since they are involved in the co/post-translational processing of peptides which are responsible for host cell invasion. Studies that consider these enzymes as targets point out the potential of benzoheterocyclic compounds as inhibitors of Candida albicans’s N-myristoyltransferase. Here we applied a combination of comparative binding site analysis and molecular docking studies based on a Piggyback approach in the search for new Leishmania major NMT ligands. Our results revealed that NMT enzymes from both pathogens present enough structural similarity to allow extrapolation of the knowledge available from C. albicans studies to develop new L. major NMT inhibitors. Molecular docking studies with benzoheterocyclic analogues indicate the potential of benzothiazole derivatives as L. major NMT ligands, giving rise to a completely new class of chemical compounds to be explored in the development of antileishmanial drugs.

利什曼病（Leishmaniasis）是亟需研发药理学替代疗法的被忽视疾病之一。在此背景下，N-肉豆蔻酰基转移酶（N-Myristoyltransferases, NMT）成为颇具研究价值的靶点，因其参与调控负责宿主细胞入侵的肽类的共/翻译后加工过程。以这类酶为靶点的研究表明，苯并杂环化合物（benzoheterocyclic compounds）可作为白色念珠菌（Candida albicans）N-肉豆蔻酰基转移酶的抑制剂，具备应用潜力。本研究采用结合比对结合位点分析与基于背负式对接策略（Piggyback approach）的分子对接（molecular docking）研究的组合方法，旨在筛选新型硕大利什曼原虫（Leishmania major）NMT配体。研究结果显示，两种病原体的NMT酶具备足够的结构相似性，因此可将白色念珠菌相关研究中积累的知识外推，用于开发新型硕大利什曼原虫NMT抑制剂。针对苯并杂环类似物开展的分子对接研究表明，苯并噻唑衍生物（benzothiazole derivatives）具备作为硕大利什曼原虫NMT配体的潜力，由此催生了一类全新的化合物，可用于抗利什曼病药物（antileishmanial drugs）的研发。