Design and synthesis of matrix metalloproteinase inhibitors guided by molecular modeling. Picking the S(1) pocket using conformationally constrained inhibitors.
Conformationally constrained MMP inhibitors based on a D-proline scaffold were designed using AutoDock as a modeling program. Thus a family of D-proline hydroxamic acids, having differentiated functionality at the site of binding to the S(1) pocket, was synthesized. Biological evaluation showed low nanomolar activity and modest selectivity toward different MMP subclasses, delineating the importance of binding to the S(1) pocket for both activity and selectivity.
Hanessian
S
S
Department of Chemistry, Université de Montréal, C. P. 6128, Succursale Centre-Ville, Montréal, P Q H3C 3J7, Canada. stephen.hanessisan@umontreal.ca
MacKay
D B
DB
Moitessier
N
N
D017364:Collagenases / Q000737:chemistry; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011392:Proline; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1