Design and synthesis of indolo[2,3-a]quinolizin-7-one inhibitors of the ZipA-FtsZ interaction.
The binding of FtsZ to ZipA is a potential target for antibacterial therapy. Based on a small molecule inhibitor of the ZipA-FtsZ interaction, a parallel synthesis of small molecules was initiated which targeted a key region of ZipA involved in FtsZ binding. The X-ray crystal structure of one of these molecules complexed with ZipA was solved. The structure revealed an unexpected binding mode, facilitated by desolvation of a loosely bound surface water.
Wyeth Research, Department of Medicinal Chemistry, 401N. Middletown Rd, Pearl River, NY 10965, USA. jenninl@wyeth.com
Lee D
LD
Jennings
Ken W
KW
Foreman
Thomas S
TS
Rush
Desiree H H
DH
Tsao
Lidia
L
Mosyak
Yuanhong
Y
Li
Mohani N
MN
Sukhdeo
Weidong
W
Ding
Elizabeth G
EG
Dushin
Cynthia Hess
CH
Kenny
Soraya L
SL
Moghazeh
Peter J
PJ
Petersen
Alexey V
AV
Ruzin
Margareta
M
Tuckman
Alan G
AG
Sutherland
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015195:Drug Design; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000502:physiology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D029968:Escherichia coli Proteins; C076835:FtsZ84 protein, E coli; D007211:Indoles; D011799:Quinazolines; C103795:ZipA protein, E coli; C475704:indolo(2,1-b)quinazoline