Triketoacid inhibitors of HIV-integrase: a new chemotype useful for probing the integrase pharmacophore.
Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. This study reports on the discovery of a new triketoacid-based chemotype that selectively inhibits the strand transfer reaction of HIV-integrase. SAR studies showed that the template binds to integrase in a manner similar to the diketoacid-based inhibitors. Moreover, comparison of the new chemotype to two different diketoacid templates led us to propose two aryl-binding domains in the inhibitor binding site. This information was used to design a new diketoacid template with improved activity against the enzyme.
Walker
Michael A
MA
Department of Medicinal Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb, The Richard L Gelb Center for Pharmaceutical Research and Development, 5 Research Parkway Wallingford, CT 06492, USA. walkerma@bms.com
Johnson
Timothy
T
Ma
Zhuping
Z
Banville
Jacques
J
Remillard
Roger
R
Kim
Oak
O
Zhang
Yunhui
Y
Staab
Andrew
A
Wong
Henry
H
Torri
Albert
A
Samanta
Himadri
H
Lin
Zeyu
Z
Deminie
Carol
C
Terry
Brian
B
Krystal
Mark
M
Meanwell
Nicholas
N
D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D019427:HIV Integrase