Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors

被引：10

作者：

Song, Lijun ^{[1
,11
]}

Merceron, Romain ^{[2
,3
,12
]}

Hulpia, Fabian ^{[1
,13
]}

Lucia, Ainhoa ^{[4
,5
,6
]}

Gracia, Begona ^{[4
,5
,6
]}

Jian, Yanlin ^{[1
]}

Risseeuw, Martijn D. P. ^{[1
]}

Verstraelen, Toon ^{[7
]}

Cos, Paul ^{[8
]}

Ainsa, Jose A. ^{[4
,5
,6
]}

Boshoff, Helena, I ^{[9
]}

Munier-Lehmann, Helene ^{[10
]}

Savvides, Savvas N. ^{[2
,3
]}

Van Calenbergh, Serge ^{[1
]}

机构：

[1] Univ Ghent, Lab Med Chem FFW, Tergestensis 460, B-9000 Ghent, Belgium

[2] VIB Ctr Inflammat Res, B-9052 Ghent, Belgium

[3] Univ Ghent, Dept Biochem & Microbiol, Technol Pk 927, B-9052 Ghent, Belgium

[4] Univ Zaragoza, Grp Genef Micobacterias, Dept Micro Biol, Fac Med, Zaragoza, Spain

[5] Univ Zaragoza, BIFI, Zaragoza, Spain

[6] Inst Salud Carlos III, CIBER Enfermedades Resp CIBERES, Madrid 28029, Spain

[7] Univ Ghent, Ctr Melecular Modeling, B-9052 Ghent, Belgium

[8] Univ Antwerp, Lab Microbiol Parasitol & Hyg LMPH, Dept Pharmaceut Sci, Campus Drie Eiken,Univ Pl 1, B-2610 Antwerp, Belgium

[9] NIAID, TB Res Sect, Lab Clin Immunol & Microbiol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[10] Inst Pasteur, CNRS, UMR3523, Dept Struct Biol & Chem, F-75724 Paris 15, France

[11] 3M, Zwijndrecht, Belgium

[12] Eurofins Grp, Poitiers, France

[13] Janssen Pharmaceut, Beerse, Belgium

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 225卷

关键词：

Mycobacterium tuberculosis; Thymidylate kinase; Structure-based inhibitor design; MYCOBACTERIUM-TUBERCULOSIS; DRUG-RESISTANCE; EFFLUX PUMP; GENERATION; VISUALIZATION; ACCUMULATION; PERMEABILITY; DISCOVERY; REVEALS; PHENOLS;

D O I：

10.1016/j.ejmech.2021.113784

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. (C) 2021 Elsevier Masson SAS. All rights reserved.

引用

页数：25

共 60 条

[31] Mycolic acid structure determines the fluidity of the mycobacterial cell wall [J].

Liu, J ;

Barry, CE ;

Besra, GS ;

Nikaido, H .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (47) :29545-29551

[32] N,N-Dimethyl glycine-promoted Ullmann coupling reaction of phenols and aryl halides [J].

Ma, DW ;

Cai, Q .

ORGANIC LETTERS, 2003, 5 (21) :3799-3802

[33] Cu-Catalyzed Arylation of Phenols: Synthesis of Sterically Hindered and Heteroaryl Diaryl Ethers [J].

Maiti, Debabrata ;

Buchwald, Stephen L. .

JOURNAL OF ORGANIC CHEMISTRY, 2010, 75 (05) :1791-1794

[34] Towards a new combination therapy for tuberculosis with next generation benzothiazinones [J].

Makarov, Vadim ;

Lechartier, Benoit ;

Zhang, Ming ;

Neres, Joao ;

van der Sar, Astrid M. ;

Raadsen, Susanne A. ;

Hartkoorn, Ruben C. ;

Ryabova, Olga B. ;

Vocat, Anthony ;

Decosterd, Laurent A. ;

Widmer, Nicolas ;

Buclin, Thierry ;

Bitter, Wilbert ;

Andries, Koen ;

Pojer, Florence ;

Dyson, Paul J. ;

Cole, Stewart T. .

EMBO MOLECULAR MEDICINE, 2014, 6 (03) :372-383

[35] Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds [J].

Makowska-Grzyska, Magdalena ;

Kim, Youngchang ;

Gorla, Suresh Kumar ;

Wei, Yang ;

Mandapati, Kavitha ;

Zhang, Minjia ;

Maltseva, Natalia ;

Modi, Gyan ;

Boshoff, Helena I. ;

Gu, Minyi ;

Aldrich, Courtney ;

Cuny, Gregory D. ;

Hedstrom, Lizbeth ;

Joachimiak, Andrzej .

PLOS ONE, 2015, 10 (10)

[36]

Mjalli A. M., 2006, PCT Int. Appl., Patent No. [WO, 2006099379, 2006099379, WO2006099379A2]

[37] AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility [J].

Morris, Garrett M. ;

Huey, Ruth ;

Lindstrom, William ;

Sanner, Michel F. ;

Belew, Richard K. ;

Goodsell, David S. ;

Olson, Arthur J. .

JOURNAL OF COMPUTATIONAL CHEMISTRY, 2009, 30 (16) :2785-2791

[38] Thymidylate kinase of Mycobacterium tuberculosis:: A chimera sharing properties common to eukaryotic and bacterial enzymes [J].

Munier-Lehmann, H ;

Chaffotte, A ;

Pochet, S ;

Labesse, G .

PROTEIN SCIENCE, 2001, 10 (06) :1195-1205

[39] Structure Guided Lead Generation for M. tuberculosis Thymidylate Kinase (Mtb TMK): Discovery of 3-Cyanopyridone and 1,6-Naphthyridin-2-one as Potent Inhibitors [J].

Naik, Maruti ;

Raichurkar, Anandkumar ;

Bandodkar, Balachandra S. ;

Varun, Begur V. ;

Bhat, Shantika ;

Kalkhambkar, Rajesh ;

Murugan, Kannan ;

Menon, Rani ;

Bhat, Jyothi ;

Paul, Beena ;

Iyer, Harini ;

Hussein, Syeed ;

Tucker, Julie A. ;

Vogtherr, Martin ;

Embrey, Kevin J. ;

McMiken, Helen ;

Prasad, Swati ;

Gill, Adrian ;

Ugarkar, Bheemarao G. ;

Venkatraman, Janani ;

Read, Jon ;

Panda, Manoranjan .

JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (02) :753-766

[40] Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria [J].

Nikaido, H .

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2001, 12 (03) :215-223

← 1 2 3 4 5 6 →