Abstract
Nicotinamide-nucleotide adenylyl transferase (Rv2421c) was selected as a potential drug target, because it has been shown, in vitro, to be essential for Mycobacterium tuberculosis growth. It is conserved between mycobacterium species, is up-regulated during dormancy, has a known 3D crystal structure and has no known human homologs. A model of Rv2421c in complex with nicotinic acid adenine dinucleotide and magnesium ion was constructed and subject tovirtual ligand screening against the Prestwick Chemical Library and the ZINC database, which yielded 155 potential hit molecules. Of the 155 compounds identified five were pursued further using an IC50 based 3D-QSAR study. The 3D-QSAR model validated the inhibition properties of the five compounds based on R2 value of 0.895 and Q2 value of 0.944 compared to known inhibitors of Rv2421c. Higher binding affinities was observed for the novel ZINC13544129 and two FDA approved compounds (Novobiocin sodium salt, Sulfasalazine). Similarly, the total interaction energy was found to be the highest for Cromolyn disodium system (-418.88 kJ/mol) followed by Novobiocin (-379.19 kJ/mol) and Sulfasalazine with (-330.13 kJ/mol) compared to substrate DND having (-185.52 kJ/mol). Subsequent in vitro testing of the five compounds identified Novobiocin sodium salt with activity against Mycobacterium tuberculosis at 50 μM, 25μM and weakly at 10μM concentrations. Novobiocin salt interacts with a MG ion and active site residues His20, Thr86, Gly107 and Leu164 similar to substrate DND of Mycobacterium tuberculosis Rv2421c. Additional in silico structural analysis of known Novobiocin sodium salt derivatives against Rv2421c suggest Coumermycin as a promising alternative for the treatment of Mycobacterium tuberculosis based on large number of hydrogen bond interactions with Rv2421c similar in comparison to Novobiocin salt and substrate DND.
Highlights
Tuberculosis (TB) is the second leading cause of death after Human Immunodeficiency virus and accounts for approximately 1.3 million deaths and 10.4 million new cases per year [1,2]
Nicotinamidenucleotide adenylyl transferase (NadD/Rv2421c) is essential for the survival of Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli (E. coli) and M. tuberculosis as all these organisms harbor both de novo and salvage pathways which is useful during ATP limited conditions [5]
Nicotinic acid mononucleotide (NaMN) adenylyl transferase (PDBID: 3E27, resolution 2.2 Å, [5]) and the coordinates of substrate DND and magnesium ion (MG) were extracted from 3E27 to construct a complex of Rv2421c with DND and MG; the structural similarity between Rv2421c and 3E27 was assessed using the root mean square deviation (RMSD) value
Summary
Tuberculosis (TB) is the second leading cause of death after Human Immunodeficiency virus and accounts for approximately 1.3 million deaths and 10.4 million new cases per year [1,2]. The remainder of latently infected individuals generate a critical reservoir of TB bacteria in their system which may result in disease reactivation should their immune system be compromised [3]. This poses a significant problem as current drugs require a long course of therapy with patients experiencing various degrees of adverse reactions [2]. The genome of M. tuberculosis is ~4.4Mb in size and codes for approximately 4000 proteins [4] Not all these proteins are potential drug targets. In a follow up study, Huang et al [6] solved crystal structures of three inhibitors bound to NadD in B.anthracis that were identified in the Sorci study [5] and revealed a common binding site near residues Trp117, Tyr112 and Met109
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