Exploring the Subtleties of Drug−Receptor Interactions:  The Case of Matrix Metalloproteinases

Abstract

By solving high-resolution crystal structures of a large number (14 in this case) of adducts of matrix metalloproteinase 12 (MMP12) with strong, nanomolar, inhibitors all derived from a single ligand scaffold, it is shown that the energetics of the ligand-protein interactions can be accounted for directly from the structures to a level of detail that allows us to rationalize for the differential binding affinity between pairs of closely related ligands. In each case, variations in binding affinities can be traced back to slight improvements or worsening of specific interactions with the protein of one or more ligand atoms. Isothermal calorimetry measurements show that the binding of this class of MMP inhibitors is largely enthalpy driven, but a favorable entropic contribution is always present. The binding enthalpy of acetohydroxamic acid (AHA), the prototype zinc-binding group in MMP drug discovery, has been also accurately measured. In principle, this research permits the planning of either improved inhibitors, or inhibitors with improved selectivity for one or another MMP. The present analysis is applicable to any drug target for which structural information on adducts with a series of homologous ligands can be obtained, while structural information obtained from in silico docking is probably not accurate enough for this type of study.

Discovery of a New Class of Potent MMP Inhibitors by Structure-Based Optimization of the Arylsulfonamide Scaffold

“…15 The theoretical free energies of binding calculated by AutoDock 17 (Supporting Information) univocally show that compounds bearing both the ethylene linker and the D-proline moiety exhibit the lowest theoretical K i values. It is interesting to note that the decrease in theoretical K i values was found to be more sensitive to the substitution of glycine with D-proline, than to the introduction of the ethylene linker between the sulfonamide moiety and the P1′ group.…”

A Highly Soluble Matrix Metalloproteinase‐9 Inhibitor for Potential Treatment of Dry Eye Syndrome

“…However, all these symptomatic treatments require frequent eye drop administrations, which decrease the patient's compliance and might lead to a social problem, especially in case of chronic therapies [20]. Therefore, new therapeutic strategies, which could overcome the need of repeated administrations, are strongly encouraged.In this paper, we propose a new, non-symptomatic approach for the treatment of DES that relies on the inhibition of MMP-9 by a novel water-soluble small molecule, namely PES_103 [1,21]. Here, we report the encouraging results obtained in vitro and in vivo by testing the efficacy of PES_103 for the treatment of DES, as well as the lack of corneal cytotoxicity, on an animal model of reduced lacrimation.…”

“…In this paper, we propose a new, non-symptomatic approach for the treatment of DES that relies on the inhibition of MMP-9 by a novel water-soluble small molecule, namely PES_103 [1,21]. Here, we report the encouraging results obtained in vitro and in vivo by testing the efficacy of PES_103 for the treatment of DES, as well as the lack of corneal cytotoxicity, on an animal model of reduced lacrimation.…”

“…The efficacy of PES_103 in vivo and the potential benefits of this treatment in restoring tear production were studied in this work using an animal model of reduced lacrimation. PES_103 did not show any significant corneal toxicity.Matrix metalloproteinases (MMPs) are a family of zinc containing hydrolases with a broad proteolytic specificity and large structural similarity [1]. These enzymes are involved in the degradation of several extracellular proteins including extracellular matrix components (ECM) and play a crucial role in tissue remodelling and in the regulation of different cellular activities [2].…”

Is there a link between selectivity and binding thermodynamics profiles?

“…Matrix metalloproteinase 12 (MMP12) inhibitors were optimized by using X-ray crystallography and thermodynamics measurements [16] while monitoring selectivity against matrix metalloproteinase 13. The highest selectivity was 5 kJ/mol in terms of G that had been achieved by the most enthalpic compound (H=-40.4 kJ/mol) and again, this was not the highest affinity compound considering the MMP12 target.…”