Correction: Effect of heterocycle content on metal binding isostere coordination.

[This corrects the article DOI: 10.1039/D0SC02717K.].

Evaluating Metal-Ligand Interactions of Metal-Binding Isosteres Using Model Complexes.

Bioisosteres are a useful approach to address pharmacokinetic liabilities and improve drug-like properties. Specific to developing metalloenzyme inhibitors, metal-binding pharmacophores (MBPs) have been combined with bioisosteres, to produce metal-binding isosteres (MBIs) as alternative scaffolds for use in fragment-based drug discovery (FBDD). Picolinic acid MBIs have been reported and evaluated for their metal-binding ability, pharmacokinetic properties, and enzyme inhibitory activity.

Effect of heterocycle content on metal binding isostere coordination.

Bioisostere replacement is a core concept in modern medicinal chemistry and has proven an invaluable strategy to address pharmacodynamic and pharmacokinetic limitations of therapeutics. The success of bioisostere replacement is often dependent on the scaffold that is being modified (, "context dependence"). The application of bioisostere replacement to a picolinic acid fragment was recently demonstrated as a means to expand a library of metal-binding pharmacophores (MBPs) to modulate their physicochemical properties, while retaining their metal binding and metalloenzyme inhibitory activity.

SAR Exploration of Tight-Binding Inhibitors of Influenza Virus PA Endonuclease.

Significant efforts have been reported on the development of influenza antivirals including inhibitors of the RNA-dependent RNA polymerase PA N-terminal (PA) endonuclease. Based on recently identified, highly active metal-binding pharmacophores (MBPs) for PA endonuclease inhibition, a fragment-based drug development campaign was pursued. Guided by coordination chemistry and structure-based drug design, MBP scaffolds were elaborated to improve activity and selectivity.

Metal-Binding Pharmacophore Library Yields the Discovery of a Glyoxalase 1 Inhibitor.

Anxiety and depression are common, highly comorbid psychiatric diseases that account for a large proportion of worldwide medical disability. Glyoxalase 1 (GLO1) has been identified as a possible target for the treatment of anxiety and depression. GLO1 is a Zn-dependent enzyme that isomerizes a hemithioacetal, formed from glutathione and methylglyoxal, to a lactic acid thioester.

Structure-Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease.

Metalloenzymes represent an important target space for drug discovery. A limitation to the early development of metalloenzyme inhibitors has been the lack of established structure-activity relationships (SARs) for molecules that bind the metal ion cofactor(s) of a metalloenzyme. Herein, we employed a bioinorganic perspective to develop an SAR for inhibition of the metalloenzyme influenza RNA polymerase PA endonuclease.

Targeting Metalloenzymes for Therapeutic Intervention.

Metalloenzymes are central to a wide range of essential biological activities, including nucleic acid modification, protein degradation, and many others. The role of metalloenzymes in these processes also makes them central for the progression of many diseases and, as such, makes metalloenzymes attractive targets for therapeutic intervention. Increasing awareness of the role metalloenzymes play in disease and their importance as a class of targets has amplified interest in the development of new strategies to develop inhibitors and ultimately useful drugs.

Metal-Binding Isosteres as New Scaffolds for Metalloenzyme Inhibitors.

The principle of isosteres or bioisosteres in medicinal chemistry is a central and essential concept in modern drug discovery. For example, carboxylic acids are often replaced by bioisosteres to mitigate issues related to lipophilicity or acidity while retaining acidic characteristics in addition to hydrogen bond donor/acceptor abilities. Separately, the development of metal-binding pharmacophores (MBPs) for binding to the active site metal ion in metalloenzymes of therapeutic interest is an emerging area in the realm of fragment-based drug discovery (FBDD).

Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition.

Hydroxypyridinethiones (HOPTOs) are strong ligands for metal ions and potentially useful pharmacophores for inhibiting metalloenzymes relevant to human disease. However, HOPTOs have been sparingly used in drug discovery efforts due, in part, to concerns that this scaffold will act as a promiscuous, non-selective metalloenzyme inhibitor, as well as possess poor pharmacokinetics (PK), which may undermine drug candidates containing this functional group. To advance HOPTOs as a useful pharmacophore for metalloenzyme inhibitors, a library of 22 HOPTO isostere compounds has been synthesized and investigated.

Isoreticular expansion of polyMOFs achieves high surface area materials.

The concept of isoreticular chemistry has become a core principle in metal-organic framework (MOF) materials. Isoreticular chemistry has shown that organic ligands of different sizes, but with a common geometry/symmetry can be used to generate MOFs of related topologies, but with expanded pore sizes and volumes. In this report, polymer-MOF hybrid materials (polyMOFs) with a UiO (UiO = University of Oslo) architecture are shown to adhere to the principle of isoreticular expansion, generating polyMOFs with large surface areas and enhanced stability.

Effect of donor atom identity on metal-binding pharmacophore coordination.

The inhibition and binding of three metal-binding pharmacophores (MBPs), 2-hydroxycyclohepta-2,4,6-trien-1-one (tropolone), 2-mercaptopyridine-N-oxide (1,2-HOPTO), and 2-hydroxycyclohepta-2,4,6-triene-1-thione (thiotropolone) to human carbonic anhydrase II (hCAII) and a mutant protein hCAII L198G were investigated. These MBPs displayed bidentate coordination to the active site Zn(II) metal ion, but the MBPs respond to the mutation of L198G differently, as characterized by inhibition activity assays and X-ray crystallography. The L198G mutation increases the active site volume thereby decreasing the steric pressure exerted on MBPs upon binding, allowing changes in MBP coordination to be observed.