Abstract
PurposeThere is an urgent need to discover and develop new drugs to combat Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) in humans. In recent years, there has been a renewed interest in the discovery of new anti-TB agents from natural sources. In the present investigation, molecular docking studies were carried out on two ellagic acid derivatives, namely pteleoellagic acid (1) isolated from Ludwigia adscendens, and 3,3′-di-O-methyl ellagic acid 4-O-α-rhamnopyranoside (2) isolated from Trewia nudiflora, to investigate their binding to two enzymes involved in M. tuberculosis cell wall biogenesis, namely 2-trans-enoyl-ACP reductase (InhA) and β-ketoacyl-ACP reductase (MabA), and to pantothenate kinase (PanK type I) involved in the biosynthesis of coenzyme A, essential for the growth of M. tuberculosis.MethodsMolecular docking experiments were performed using AutoDock Vina.The crystal structures of InhA, MabA and PanK were retrieved from the RCSB Protein Data Bank (PDB). Isonicotinic-acyl-NADH for InhA and MabA, and triazole inhibitory compound for PanK, were used as references.ResultsPteleoellagic acid showed a high docking score, estimated binding free energy of −9.4 kcal/mol, for the MabA enzyme comparable to the reference compound isonicotinic-acyl-NADH.ConclusionsKnowledge on the molecular interactions of ellagic acid derivatives with essential M. tuberculosis targets could prove a useful tool for the design and development of future anti-TB drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s40203-015-0014-1) contains supplementary material, which is available to authorized users.
Highlights
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) in humans, is the leading bacterial killer worldwide
Several key enzymes involved in M. tuberculosis cell wall biogenesis and physiological functions have become attractive targets for the design of novel anti-TB agents (Jackson et al 2013)
Both enzymes are functionally and structurally-related. They display the same specificity for long chain substrates and are inhibited by the front-line anti-TB drug isoniazid (Quemard et al 1995; Marrakchi et al 2000, 2002; Ducasse-Cabanot et al 2004). Another target for the development of novel anti-TB drugs is the enzyme pantothenate kinase (PanK, type I) involved in the biosynthesis of the cofactor Coenzyme A (CoA) from pantothenic acid, which is essential for the growth of M. tuberculosis (Bjorkelid et al 2013)
Summary
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) in humans, is the leading bacterial killer worldwide. Two of the target proteins of interest in this study, namely 2-trans-enoyl-ACP reductase (InhA) and β-ketoacyl-ACP reductase (MabA), belong to the type-II fatty acid elongation system (FAS-II) The latter is a complex group of enzymes responsible for the production of very long chain fatty acid derivatives that are key precursors to mycolic acids, the main constituents of M. tuberculosis cell wall (Marrakchi et al 2000, 2002; Takayama et al 2005). They display the same specificity for long chain substrates and are inhibited by the front-line anti-TB drug isoniazid (Quemard et al 1995; Marrakchi et al 2000, 2002; Ducasse-Cabanot et al 2004) Another target for the development of novel anti-TB drugs is the enzyme pantothenate kinase (PanK, type I) involved in the biosynthesis of the cofactor Coenzyme A (CoA) from pantothenic acid, which is essential for the growth of M. tuberculosis (Bjorkelid et al 2013)
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