In silico repurposing of a Novobiocin derivative for activity against latency associated Mycobacterium tuberculosis drug target nicotinate-nucleotide adenylyl transferase (Rv2421c)

被引：4

作者：

Cloete, Ruben ^{[1
]}

Shahbaaz, Mohd ^{[1
]}

Grobbelaar, Melanie ^{[2
]}

Sampson, Samantha L. ^{[2
]}

Christoffels, Alan ^{[1
]}

机构：

[1] Univ Western Cape, South African Natl Bioinformat Inst, South African Med Res Council, Bioinformat Unit, Bellville, South Africa

[2] Stellenbosch Univ, South African Med Res Council, DST NRF Ctr Excellence Biomed TB Res, Ctr TB Res,Fac Med & Hlth Sci,Div Mol Biol & Huma, Cape Town, South Africa

来源：

PLOS ONE | 2021年 / 16卷 / 11期

基金：

英国医学研究理事会; 新加坡国家研究基金会;

关键词：

MONONUCLEOTIDE ADENYLYLTRANSFERASE; HIGH-THROUGHPUT; DNA GYRASE; INHIBITORS; EFFICIENT; TOOL;

D O I：

10.1371/journal.pone.0259348

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 R-2 value of 0.895 and Q(2) 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 mu M, 25 mu M and weakly at 10 mu M 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.

引用

页数：14