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Scholarly Works (10 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2020)

A major shortcoming to the field of metalloenzyme inhibition has been the application of the same metal-binding pharmacophores (MBPs). Using novel MBPs for metalloenzyme inhibition has become an increasingly important strategy that overcomes the deficits encountered in the development of novel metalloenzyme inhibitors. Unfortunately, some functional groups utilized by MBPs may become problematic for further drug development. To help circumvent this issue and expand the range of chemical matter utilized in MBPs, this dissertation describes efforts to apply and study bioisostere/isostere replacement to MBPs and create isosteric MBPs with varied physicochemical properties, so-called metal-binding isosteres (MBIs).

Chapter 2 describes the study of the effect of MBP donor atom identity on coordination to metalloenzyme active sites. Utilizing the model protein system human carbonic anhydrase II (hCAII), upon introduction of an active site mutation changes in MBP coordination based on donor atom identity were observed.

The application of isostere replacement to MBPs was evaluated in Chapter 3. The MBP picolinic acid (pyridine-2-carboxylic acid) was studied utilizing a range of carboxylic acid isosteres to develop a series of metal-binding isosteres (MBIs). These novel metal-binding fragments afforded a range of physicochemical properties while retaining metal coordination ability and metalloenzyme inhibitory activity.

In Chapter 4, a broader study of the application of carboxylic acid isostere replacement on MBPs is described. A series of complex nitrogen containing heterocycles with varying heteroatom content and arrangement were evaluated as MBI scaffolds. The success of isostere replacements on the studied scaffolds was manipulated based on specific heteroatoms and their arrangement within the heterocycle.

Chapter 5 describes a structure-based inhibitor development campaign for the influenza polymerase acidic N-terminal endonuclease domain (Endo) of the RNA-dependent RNA polymerase complex. The optimization, using scaffold modification and isostere replacement, of a potent MBP was undertaken based on observed coordination modes from protein crystal structures.

    Cover page: Exploring and Expanding the Coordination Chemistry of Metal-Binding Pharmacophores for Metalloenzyme Inhibition
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2018)
    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). The direct application of the bioisostere concept to MBPs has not been well-described or systematically investigated. Herein, the picolinic acid MBP is used as a case study for the development of MBP isosteres (so-called MBIs). Many of these isosteres are novel compounds, and data on their physicochemical properties, metal binding capacity, and metalloenzyme inhibition characteristics are presented. The results show that MBIs of picolinic acid generally retain metal coordinating properties and exhibit predictable metalloenzyme inhibitory activity while possessing a broad range of physicochemical properties (e.g., p Ka, log P). These findings demonstrate the use of bioisosteres results in an untapped source of metal binding functional groups suitable for metalloenzyme FBDD. These MBIs provide a previously unexplored route for modulating the physicochemical properties of metalloenzyme inhibitors and improving their drug-likeness.
      Cover page: Metal-Binding Isosteres as New Scaffolds for Metalloenzyme Inhibitors
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2020)
      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 (i.e., "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. Here, metal binding isosteres (MBIs) with different nitrogen-containing heteroarenes is explored. This resulted in a number of new MBIs that were evaluated for their physicochemical properties and metal binding features. It was observed that the coordination behavior of an MBI is dependent on the identity and arrangement of the heteroatoms within each heteroarene. To further understand the observed coordination chemistry trends, density functional theory (DFT) calculations were performed. Theory indicates that preferences in coordination geometry are largely determined by the electronic character of the heteroarene scaffold. These results provide important insights into the development of novel MBI scaffolds that can serve to broaden the scope of scaffolds for metalloenzyme inhibitor development.
        Cover page: Effect of heterocycle content on metal binding isostere coordination
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2022)
        [This corrects the article DOI: 10.1039/D0SC02717K.].
          Cover page: Correction: Effect of heterocycle content on metal binding isostere coordination
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2021)
          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. However, their structural, electronic, and spectroscopic properties with metal ions other than Zn(II) have not been reported, which might reveal similarities and differences between MBIs and the parent MBPs. To this end, [M(TPA)(MBI)]+ (M = Ni(II) and Co(II), TPA = tris(2-pyridylmethyl)amine) is presented as a bioinorganic model system for investigating picolinic acid, four heterocyclic MBIs, and 2,2'-bipyridine. These complexes were characterized by X-ray crystallography as well as NMR, IR, and UV-vis spectroscopies, and their magnetic moments were accessed. In addition, [(TpPh,Me)Co(MBI)] (TpPh,Me = hydrotris(3,5-phenylmethylpyrazolyl)borate) was used as a second model compound, and the limitations and attributes of the two model systems are discussed. These results demonstrate that bioinorganic model complexes are versatile tools for metalloenzyme inhibitor design and can provide insights into the broader use of MBIs.
            Cover page: Evaluating Metal–Ligand Interactions of Metal-Binding Isosteres Using Model Complexes
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2017)
            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. When comparing the binding mode of tropolone to thiotropolone or 1,2-HOPTO (O,O versus O,S donor sets), structural modifications of the hCAII active site were shown to have a stronger effect on MBPs with an O,O versus O,S donor set. These findings were corroborated with density functional theory (DFT) calculations of model coordination complexes. These results suggest that the MBP binding geometry is a malleable interaction, particularly for certain ligands, and that the identity of the donor atoms influences the response of the ligand to changes in the protein active site environment. Understanding underlying interactions between a MBP and a metalloenzyme active site may aid in the design and development of potent metalloenzyme inhibitors.
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2018)
              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. This library demonstrates that it is possible to maintain the core metal-binding pharmacophore (MBP) while generating diversity in structure, electronics, and PK properties. This HOPTO library has been screened against a set of four different metalloenzymes, demonstrating that while the same metal-binding donor atoms are maintained, there is a wide range of activity between metalloenzyme targets. Overall, this work shows that HOPTO isosteres are useful MBPs and valuable scaffolds for metalloenzyme inhibitors.
                Cover page: Isosteres of hydroxypyridinethione as drug-like pharmacophores for metalloenzyme inhibition
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2019)
                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. In this Review, we provide a broad overview of several drug discovery efforts focused on metalloenzymes and attempt to map out the current landscape of high-value metalloenzyme targets.
                  Cover page: Targeting Metalloenzymes for Therapeutic Intervention
                  • Article
                  • Peer Reviewed
                  UC San Diego Previously Published Works (2018)
                  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 PAN endonuclease. The identified trends highlight the importance of the electronics of the metal-binding pharmacophore (MBP), in addition to MBP sterics, for achieving improved inhibition and selectivity. By optimization of the MBPs for PAN endonuclease, a class of highly active and selective fragments was developed that displays IC50 values <50 nM. This SAR led to structurally distinct molecules that also displayed IC50 values of ∼10 nM, illustrating the utility of a metal-centric development campaign in generating highly active and selective metalloenzyme inhibitors.
                    Cover page: Structure–Activity Relationships in Metal-Binding Pharmacophores for Influenza Endonuclease
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2019)
                    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 Zn2+-dependent enzyme that isomerizes a hemithioacetal, formed from glutathione and methylglyoxal, to a lactic acid thioester. To develop active inhibitors of GLO1, fragment-based drug discovery was used to identify fragments that could serve as core scaffolds for lead development. After screening a focused library of metal-binding pharmacophores, 8-(methylsulfonylamino)quinoline (8-MSQ) was identified as a hit. Through computational modeling and synthetic elaboration, a potent GLO1 inhibitor was developed with a novel sulfonamide core pharmacophore. A lead compound was demonstrated to penetrate the blood-brain barrier, elevate levels of methylglyoxal in the brain, and reduce depression-like behavior in mice. These findings provide the basis for GLO1 inhibitors to treat depression and related psychiatric illnesses.
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