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THE SYNTHESES AND EVALUATIONS ON THE BINDING OF LINKAGE LIGANDS AS INHIBITORS OF ACETYLCHOLINESTERASE AND MATRIX METALLOPROTEINASE-3
- Abstract:
- Ph.D. Dissertation Defense
Dimerization of tacrine (THA), a weak inhibitor of acetylcholinesterase (AChE) used to treat Alzheimer’s disease, greatly enhanced the binding to AChE. However, an unambiguous mechanistic explanation of this increased potency is unavailable. The evaluation of a series of bivalent and trivalent ligands is reported here. The inhibitory potencies of THA-based dimers were enhanced 6-fold over THA. Surprisingly, the corresponding trimer was found to have no advantage in potency over THA, and the propidium-based dimer was the weakest inhibitor. The IC50 values of THA-based dimers remaining constant regardless of AChE concentration change indicated that their aromatic domains simultaneously bind at the separate segments of a single binding site. Evidences from dynamic light scattering also supported an intramolecular binding model.
The matrix metalloproteinases (MMPs) are a family of zinc dependent enzymes that mediate the breakdown of connective tissues. The development of highly specific MMP inhibitors is of special interest for the treatment of myriad diseases caused by dysregulation of MMPs. Many potent MMP inhibitors possess conceptually distinct moieties that simultaneously fit into the discrete binding pockets in the catalytic domain of MMP. Specifically, we studied a series of MMP-3 inhibitors containing a hydroxamic acid and a few hydrophobic moieties with affinity for the catalytic Zn2+ and discrete binding pockets, respectively. We examined the energetic contributions from the fragments of the parent linkage ligand and the nature of interaction energies calorimetrically. The additivity analyses indicated that high potencies of most linkage ligands arise primarily from enthalpic effects. The introduction of an isopropyl group in certain ligands results a less favorable enthalpy, which may be attributed to the gauche interaction between the isopropyl and the pyridylmethyl group.
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