Molecular Recognition of the Catalytic Zinc(II) Ion in MMP-13: Structure-Based Evolution of an Allosteric Inhibitor to Dual Binding Mode Inhibitors with Improved Lipophilic Ligand Efficiencies

Abstract

Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91).

Design and Structural Evolution of Matrix Metalloproteinase Inhibitors

“…The aliphatic linker protrudes from the S1' pocket and chelates the catalytic zinc(II) ionw ith the carboxylic acid moiety. [156] Further developmento f56 yieldedf luorinated compound 57,w hich shares as imilar binding geome-try in molecularm odelinge xperiments. Alteration of the substitutionp attern of the aliphatic linker from meta to para at the entrance of the S1' pocket and implementation of af luorine atom within the S1'*l oop resulted in ah ighly potent MMP-13 inhibitor with an IC 50 value of 6nm.…”

Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors

“…[41][42][43][44][45][46][47] Historically, most MMP inhibitors gained affinity through interacting with the catalytic zinc via a chelating moiety and by positioning hydrogen bonding groups such as backbone NH of Leu185, backbone carbonyl oxygen of Ala186, and carboxylate of the Glu202 residue near the catalytic zinc. However, one major concern with this approach is the issue of selectivity, since many of the important residues in the catalytic site are well-conserved among the MMP family.…”

(2-Aminobenzothiazole)-Methyl-1,1-Bisphosphonic Acids: Targeting Matrix Metalloproteinase 13 Inhibition to the Bone

“…Selective inhibitors of MMP-13 were developed over the years that, instead of binding the zinc ion, exploit the interaction with an accessory pocket named S1′* [ 3 , 25 ]. Although the latest research efforts in the field of MMP-13 inhibitors focused on the development of nonzinc-binding ligands, a recent approach, involving the introduction of a zinc-binding group to an otherwise nonzinc-binding class of compounds, yielded compounds capable of selectively inhibiting this enzyme in the submicromolar range [ 26 ].…”