Influenza neuraminidase inhibitors: structure-based design of a novel inhibitor series.
Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K(i) = 58 microM via a potency enhancement of >70 000-fold to an analogue with an activity of K(i) = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure-activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180 degrees variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.
Stoll
Vincent
V
Department of Advanced Technology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA.
Stewart
Kent D
KD
Maring
Clarence J
CJ
Muchmore
Steven
S
Giranda
Vincent
V
Gu
Yu-gui Y
YG
Wang
Gary
G
Chen
Yuanwei
Y
Sun
Minghua
M
Zhao
Chen
C
Kennedy
April L
AL
Madigan
Darold L
DL
Xu
Yibo
Y
Saldivar
Ayda
A
Kati
Warren
W
Laver
Graeme
G
Sowin
Thomas
T
Sham
Hing L
HL
Greer
Jonathan
J
Kempf
Dale
D
D000588:Amines / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D001717:Birds; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D003460:Crystallization; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004952:Esters; D009980:Influenza A virus / Q000201:enzymology*; D008958:Models, Molecular; D036103:Nanotechnology / Q000379:methods; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000302:isolation & purification; D011759:Pyrrolidines / Q000138:chemical synthesis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000588:Amines; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D004952:Esters; D011759:Pyrrolidines; D009439:Neuraminidase