Improvement of the novel inhibitor for Mycobacterium enoyl-acyl carrier protein reductase (InhA): a structure-activity relationship study of KES4 assisted by in silico structure-based drug screening.
Journal
The Journal of antibiotics
ISSN: 1881-1469
Titre abrégé: J Antibiot (Tokyo)
Pays: England
ID NLM: 0151115
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
28
11
2019
accepted:
10
02
2020
revised:
09
01
2020
pubmed:
11
3
2020
medline:
29
10
2020
entrez:
11
3
2020
Statut:
ppublish
Résumé
InhA or enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis (mtInhA), which controls mycobacterial cell wall construction, has been targeted in the development of antituberculosis drugs. Previously, our in silico structure-based drug screening study identified a novel class of compounds (designated KES4), which is capable of inhibiting the enzymatic activity of mtInhA, as well as mycobacterial growth. The compounds are composed of four ring structures (A-D), and the MD simulation predicted specific interactions with mtInhA of the D-ring and methylene group between the B-ring and C-ring; however, there is still room for improvement in the A-ring structure. In this study, a structure-activity relationship study of the A-ring was attempted with the assistance of in silico docking simulations. In brief, the virtual chemical library of A-ring-modified KES4 was constructed and subjected to in silico docking simulation against mtInhA using the GOLD program. Among the selected candidates, we achieved synthesis of seven compounds, and the bioactivities (effects on InhA activity and mycobacterial growth and cytotoxicity) of the synthesized molecules were evaluated. Among the compounds tested, two candidates (compounds 3d and 3f) exhibited superior properties as mtInhA-targeted anti-infectives for mycobacteria than the lead compound KES4.
Identifiants
pubmed: 32152525
doi: 10.1038/s41429-020-0293-6
pii: 10.1038/s41429-020-0293-6
doi:
Substances chimiques
Antitubercular Agents
0
Bacterial Proteins
0
Oxidoreductases
EC 1.-
InhA protein, Mycobacterium
EC 1.3.1.9
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
372-381Références
Dye C, Williams BG. The population dynamics and control of tuberculosis. Science. 2010;328:856–61.
doi: 10.1126/science.1185449
Das P, Horton R. Tuberculosis-time to accelerate progress. Lancet. 2010;375:1755–7.
doi: 10.1016/S0140-6736(10)60600-9
Das P, Horton R. Tuberculosis-getting to zero. Lancet. 2015;386:2231–2.
doi: 10.1016/S0140-6736(15)00401-8
Lönnroth K, Castro KG, Chakaya JM, Chauhan LS, Floyd K, Glaziou P, et al. Tuberculosis control and elimination 2010-50: cure, care, and social development. Lancet. 2010;375:1814–29.
doi: 10.1016/S0140-6736(10)60483-7
Sotgiu G, Centis R, D’Ambrosio L, Migliori GB. Tuberculosis treatment and drug regimens. Cold Spring Harb Perspect Med. 2015;5:a017822.
doi: 10.1101/cshperspect.a017822
Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, et al. InhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994;263:227–30.
doi: 10.1126/science.8284673
Parikh SL, Xiao G, Tonge PJ. Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. Biochemistry. 2000;39:7645–50.
doi: 10.1021/bi0008940
McMurry LM, McDermott PF, Levy SB. Genetic evidence that InhA of Mycobacterium smegmatis is a target for triclosan. Antimicrob Agents Chemother. 1999;43:711–3.
doi: 10.1128/AAC.43.3.711
Quemard A, Sacchettini JC, Dessen A, Vilcheze C, Bittman R, Jacobs WR Jr, et al. Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. Biochemistry. 1995;34:8235–41.
doi: 10.1021/bi00026a004
Brennan PJ, Nikaido H. The envelope of mycobacteria. Annu Rev Biochem. 1995;64:29–63.
doi: 10.1146/annurev.bi.64.070195.000333
Tonge PJ, Kisker C, Slayden RA. Development of modern InhA inhibitors to combat drug resistant strains of Mycobacterium tuberculosis. Curr Top Med Chem. 2007;7:489–98.
doi: 10.2174/156802607780059781
Rotta M, Pissinate K, Villela AD, Back DF, Timmers LF, et al. Piperazine derivatives: synthesis, inhibition of the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase and SAR studies. Eur J Med Chem. 2015;90:36–447.
doi: 10.1016/j.ejmech.2014.11.034
Vilcheze C, Morbidoni HR, Weisbrod TR, Iwamoto H, Kuo M, et al. Inactivation of the inhA-encoded fatty acid synthase II (FASII) enoyl-acyl carrier protein reductase induces accumulation of the FASI end products and cell lysis of Mycobacterium smegmatis. J Bacteriol. 2000;182:59–4067.
doi: 10.1128/JB.182.14.4059-4067.2000
Oliveira JS, Pereira JH, Canduri F, Rodrigues NC, de Souza ON, de Azevedo WF Jr, et al. Crystallographic and pre-steady-state kinetics studies on binding of NADH to wild-type and isoniazid-resistant enoyl-ACP(CoA) reductase enzymes from Mycobacterium tuberculosis. J Mol Biol. 2006;359:646–66.
doi: 10.1016/j.jmb.2006.03.055
Taira J, Ito T, Nakatani H, Umei T, Baba H, Kawashima S, et al. In silico structure-based drug screening of novel antimycobacterial pharmacophores by DOCK-GOLD tandem screening. Int J Mycobacteriol. 2017;6:142–8.
doi: 10.4103/ijmy.ijmy_24_17
Taira J, Morita K, Kawashima S, Umei T, Baba H, Maruoka T, et al. Identification of a novel class of small compounds with anti-tuberculosis activity by in silico structure-based drug screening. J Antibiot. 2017;70:1057–64.
doi: 10.1038/ja.2017.106
Kinjo T, Koseki Y, Kobayashi M, Yamada A, Morita K, Yamaguchi K, et al. Identification of compounds with potential antibacterial activity against Mycobacterium through structure-based drug screening. J Chem Inf Model. 2013;53:1200–12.
doi: 10.1021/ci300571n
Koseki Y, Kinjo T, Kobayashi M, Aoki S. Identification of novel antimycobacterial chemical agents through the in silico multi-conformational structure-based drug screening of a large-scale chemical library. Eur J Med Chem. 2013;60:333–39.
doi: 10.1016/j.ejmech.2012.12.012
Kanetaka H, Koseki Y, Taira J, Umei T, Komatsu H, Sakamoto H, et al. Discovery of InhA inhibitors with anti-mycobacterial activity through a matched molecular pair approach. Eur J Med Chem. 2015;94:378–85.
doi: 10.1016/j.ejmech.2015.02.062
He X, Alian A, Stroud R, Ortiz, de Montellano PR. Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J Med Chem. 2006;49:6308–23.
doi: 10.1021/jm060715y
Kobayashi M, Kinjo T, Koseki Y, Bourne CR, Barrow WW, Aoki S. Identification of novel potential antibiotics against Staphylococcus using structure-based drug screening targeting dihydrofolate reductase. J Chem Inf Model. 2014;54:1242–53.
doi: 10.1021/ci400686d
Koseki Y, Aoki S. Computational medicinal chemistry for rational drug design: Identification of novel chemical structures with potential anti-tuberculosis activity. Curr Top Med Chem. 2014;14:176–88.
doi: 10.2174/1568026613666131113155042
Schmidt CW. TOX 21: new dimensions of toxicity testing. Environ Health Perspect. 2009;117:A348.
doi: 10.1289/ehp.0800096
Faulon JL, Visco DP, Pophale RS. The signature molecular descriptor. 1. Using extended valence sequences in QSAR and QSPR studies. J Chem Info Comput Sci. 2003;43:707–20.
doi: 10.1021/ci020345w
Berenger F. MolEnc: a molecular encoder using rdkit and OCaml. 2019. https://github.com/UnixJunkie/molenc . Accessed 19 Nov 2019.
Breiman L. Bagging predictors. Mach Learn. 1996;24:123–40.
Platt J. Probabilistic outputs for support vector machines and comparisons to regularized likelihood methods. Adv Large Margin Classif. 1999;10:61–74.
Molle V, Gulten G, Vilcheze C, Veyron-Churlet R, Zanella-Cleon I, Sacchettini JC, et al. Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis. Mol Microbiol. 2010;78:1591–605.
doi: 10.1111/j.1365-2958.2010.07446.x
Delaine T, Bernardes-Génisson V, Quémard A, Constant P, Meunier B, et al. Development of isoniazide NAD truncated adducts embedding a lipophilic fragment as potential bi-substrate InhA inhibitors and antimycobacterial agents. Eur J Med Chem. 2010;45:4554–61.
doi: 10.1016/j.ejmech.2010.07.016
Jones G, Willett P, Glen RC. Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation. J Mol Biol. 1995;245:43–53.
doi: 10.1016/S0022-2836(95)80037-9
Jones G, Willett P, Glen RC, Leach AR, Taylor R. Development and validation of a genetic algorithm for flexible docking. J Mol Biol. 1997;267:727–48.
doi: 10.1006/jmbi.1996.0897