Structure-guided design of antibacterials that allosterically inhibit DNA gyrase

被引：23

作者：

Thalji, Reema K. ^{[1
]}

Raha, Kaushik ^{[1
]}

Andreotti, Daniele ^{[2
]}

Checchia, Anna ^{[2
]}

Cui, Haifeng ^{[1
]}

Meneghelli, Giovanni ^{[2
,5
]}

Profeta, Roberto ^{[2
,5
]}

Tonelli, Federica ^{[2
]}

Tommasi, Simona ^{[2
,5
]}

Bakshi, Tania ^{[1
]}

Donovan, Brian T. ^{[1
]}

Howells, Alison ^{[3
]}

Jain, Shruti ^{[3
]}

Nixon, Christopher ^{[1
]}

Quinque, Geoffrey ^{[1
]}

McCloskey, Lynn ^{[1
]}

Bax, Benjamin D. ^{[4
,6
]}

Neu, Margarete ^{[4
]}

Chan, Pan F. ^{[1
]}

Stavenger, Robert A. ^{[1
]}

机构：

[1] GlaxoSmithKline, Collegeville, PA 19426 USA

[2] EVOTEC Ctr Drug Discovery & Dev, I-37135 Verona, Italy

[3] Inspiralis Ltd, Innovat Ctr, Norwich NR4 7GJ, Norfolk, England

[4] GlaxoSmithKline, Stevenage SG1 2NYH, Herts, England

[5] FIS, I-36075 Vicenza, Italy

[6] Cardiff Univ, Med Discovery Inst, Main Bldg,Pk Pl, Cardiff CF10 3AT, S Glam, Wales

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2019年 / 29卷 / 11期

关键词：

Antibacterial; Topoisomerase; CLEAVAGE COMPLEXES;

D O I：

10.1016/j.bmcl.2019.03.029

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.

引用

页码：1407 / 1412

页数：6

共 50 条

[21] Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains
Zhang, Guangtao
Plotnikov, Alexander N.
Rusinova, Elena
Shen, Tong
Morohashi, Keita
Joshua, Jennifer
Zeng, Lei
Mujtaba, Shiraz
Ohlmeyer, Michael
Zhou, Ming-Ming
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (22) : 9251 - 9264
[22] Structure-guided design of a high-affinity ligand for a riboswitch
Huang, Lin
Wang, Jia
Wilson, Timothy J.
Lilley, David M. J.
RNA, 2019, 25 (04) : 423 - 430
[23] Structure-guided design of a potent Clostridiodes difficile toxin A inhibitor
Hussack, Greg
Rossotti, Martin A.
van Faassen, Henk
Murase, Tomohiko
Eugenio, Luiz
Schrag, Joseph D.
Ng, Kenneth K. -S.
Tanha, Jamshid
FRONTIERS IN MICROBIOLOGY, 2023, 14
[24] Structure-Guided Design of a Peptide Lock for Modular Peptide Binders
Ernst, Patrick
Zosel, Franziska
Reichen, Christian
Nettels, Daniel
Schuler, Benjamin
Plueckthun, Andreas
ACS CHEMICAL BIOLOGY, 2020, 15 (02) : 457 - 468
[25] The transcriptome of Balamuthia mandrillaris trophozoites for structure-guided drug design
Isabelle Q. Phan
Christopher A. Rice
Justin Craig
Rooksana E. Noorai
Jacquelyn R. McDonald
Sandhya Subramanian
Logan Tillery
Lynn K. Barrett
Vijay Shankar
James C. Morris
Wesley C. Van Voorhis
Dennis E. Kyle
Peter J. Myler
Scientific Reports, 11
[26] Structure-guided design of β-secretase (BACE-1) inhibitors
McGaughey, Georgia B.
Holloway, M. Katharine
EXPERT OPINION ON DRUG DISCOVERY, 2007, 2 (08) : 1129 - 1138
[27] Structure-guided design of next-generation malaria vaccine
Julien, Jean-Philippe
ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES, 2021, 77 : C2 - C2
[28] Structure-guided design of peptide-based tryptase inhibitors
McGrath, ME
Sprengeler, PA
Hirschbein, B
Somoza, JR
Lehoux, I
Janc, JW
Gjerstad, E
Graupe, M
Estiarte, A
Venkataramani, C
Liu, Y
Yee, R
Ho, JD
Green, MJ
Lee, CS
Liu, L
Tai, V
Spencer, J
Sperandio, D
Katz, BA
BIOCHEMISTRY, 2006, 45 (19) : 5964 - 5973
[29] Structure-Guided Design for Agonist Selectivity with α7-nAChRs
Camacho-Hernandez, Gisela Andrea
Kaczanowska, Katarzyna
Harel, Michal
Beck, Christina
Doan, Lisa
Binding, Hanna
Taylor, Palmer
FASEB JOURNAL, 2017, 31
[30] Structure-Guided Design of a High Affinity Inhibitor to Human CtBP
Hilbert, Brendan J.
Morris, Benjamin L.
Ellis, Keith C.
Paulsen, Janet L.
Schiffer, Celia A.
Grossman, Steven R.
Royer, William E., Jr.
ACS CHEMICAL BIOLOGY, 2015, 10 (04) : 1118 - 1127

← 1 2 3 4 5 →