Novel 1-hydroxypiperazine-2,6-diones as new leads in the inhibition of metalloproteinases.
New compounds containing a novel zinc-binding group (1-hydroxypiperazine-2,6-dione, HPD) have been identified as effective inhibitors of matrix metalloproteinases (MMPs), with activities in the nanomolar concentration range. That moiety seemed to bind the catalytic zinc ion of MMPs, revealing itself as a new potential substitute for the hydroxamate group in the next generation of metalloproteinase inhibitors. The X-ray crystal structure of 1b elucidated its 3D conformation and supramolecular packing in solid state. Theoretical procedures were used to investigate the binding mode of this class of compounds, within the active site of MMP13. A computational method involving docking and hybrid quantum mechanical and molecular mechanical (QM/MM) dynamic simulations was developed and applied. This study suggested that the HPD moiety binds bidentately to the catalytic zinc through its oxygen atoms. The final structure obtained will allow straightforward drug design approaches in view of further optimization and development of new MMP inhibitors bearing the HPD moiety.
Centro de Quı́mica Estrutural, Instituto Superior Técnico, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
Sérgio M
SM
Marques
Tiziano
T
Tuccinardi
Elisa
E
Nuti
Salvatore
S
Santamaria
Vânia
V
André
Armando
A
Rossello
Adriano
A
Martinelli
M Amélia
MA
Santos
D001463:Barbiturates / Q000138:chemical synthesis / Q000737:chemistry; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006801:Humans; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001463:Barbiturates; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011994:Recombinant Proteins