Structure-based design and synthesis of novel non-zinc chelating MMP-12 inhibitors.
A new class of MMP-12 inhibitors was discovered and optimized using structure-based drug design methods. Modeling studies using a known MMP-12 crystal structure identified a new interaction mode for these new MMP-12 inhibitors. Further optimization resulted in the discovery of a compound displaying nanomolar activity against MMP-12 and which was co-crystallized with MMP-12.
Dublanchet
Anne-Claude
AC
Department of Chemistry, Pfizer Global Research and Development, Fresnes Laboratories, 3-9 rue de la Loge, BP 100, F-94265 Fresnes Cedex, France. anne-claude.dublanchet@wanadoo.fr
Ducrot
Pierre
P
Andrianjara
Charles
C
O'Gara
Margaret
M
Morales
Renaud
R
Compère
Delphine
D
Denis
Alexis
A
Blais
Stéphane
S
Cluzeau
Philippe
P
Courté
Karine
K
Hamon
Jacques
J
Moreau
François
F
Prunet
Marie-Laure
ML
Tertre
Anita
A
D001665:Binding Sites; D002614:Chelating Agents / Q000737:chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D015032:Zinc