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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2024)

Fragment-based drug discovery (FBDD) is a powerful approach for identifying molecules that inhibit therapeutically relevant targets, focusing on the elaboration of fragment 'hits' into compounds with enhanced inhibition and desirable pharmaceutical attributes. A significant challenge in metalloenzyme inhibition within FBDD is the repeated use of the same metal-binding pharmacophores (MBPs), which limits the development of novel inhibitors. This thesis presents innovative strategies for exploring and expanding the fragment library, aimed at developing inhibitors for metalloenzymes and thus overcoming existing limitations. It also demonstrates how the enhanced fragment libraries have facilitated the identification of hit compounds targeting therapeutically relevant metalloenzymes. Metal-binding isosteres (MBIs) are introduced as a strategy to diversify fragment libraries for metalloenzyme inhibition. Isosteric replacement with 8-hydroxyquinoline was explored to enhance the potency and selectivity of drug-target interactions, as well as to broaden physicochemical properties of the fragments. Subsequently, this thesis includes an exploration of bioinorganic model complexes to study the structural and electronic characteristics of MBIs. MBIs of picolinic acid were investigated within different bioinorganic model systems, offering new insights into their properties. Furthermore, the strategic design of thioamide, thiourea, and thiocarbamate MBPs as potent warheads was showcased. Their potential in addressing the challenges of thiol-based MBPs, specifically against Zn(II)-dependent metalloenzymes, was demonstrated.I Lastly, the discovery of small molecule inhibitors against Cu-only Superoxide Dismutase (SOD5) demonstrates the identification and development of MBP/MBI warheads for a novel antifungal target. This significantly advances the quest for antifungal agents, underscoring the thesis's contribution to the development of metalloenzyme inhibitors through fragment-based strategies.

    Cover page: Expanded Tools and Isosteres for Fragment-Based Drug Discovery against Metalloenzymes
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2023)
    Thioamides, thioureas, and thiocarbamates are introduced as stable, sulfur-based metal-binding pharmacophores (MBPs) for use in metalloenzyme fragment-based drug discovery (mFBDD). MBP reactivity, bioactivity, and structural studies show that these molecules can act as ligands for Zn(II)-dependent metalloenzymes including human carbonic anhydrase II (hCAII) and matrix metalloproteinase-2 (MMP-2).
      Cover page: Masking thiol reactivity with thioamide, thiourea, and thiocarbamate-based MBPs.
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2022)
      The use of metal-binding pharmacophores (MBPs) in fragment-based drug discovery has proven effective for targeted metalloenzyme drug development. However, MBPs can still suffer from pharmacokinetic liabilities. Bioisostere replacement is an effective strategy utilized by medicinal chemists to navigate these issues during the drug development process. The quinoline pharmacophore and its bioisosteres, such as quinazoline, are important building blocks in the design of new therapeutics. More relevant to metalloenzyme inhibition, 8-hydroxyquinoline (8-HQ) and its derivatives can serve as MBPs for metalloenzyme inhibition. In this report, 8-HQ isosteres are designed and the coordination chemistry of the resulting metal-binding isosteres (MBIs) is explored using a bioinorganic model complex. In addition, the physicochemical properties and metalloenzyme inhibition activity of these MBIs were investigated to establish drug-like profiles. This report provides a new group of 8-HQ-derived MBIs that can serve as novel scaffolds for metalloenzyme inhibitor development with tunable, and potentially improved, physicochemical properties.
        Cover page: Developing Metal-Binding Isosteres of 8‑Hydroxyquinoline as Metalloenzyme Inhibitor Scaffolds
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2023)
        Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn2+ active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PAN using a FRET-based enzymatic assay, and their mode of binding in PAN was determined using X-ray crystallography.
          Cover page: Carboxylic Acid Isostere Derivatives of Hydroxypyridinones as Core Scaffolds for Influenza Endonuclease Inhibitors
          • 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 (2021)
            This study demonstrates the screening of a collection of twelve 19F-tagged metal-binding pharmacophores (MBPs) against the Zn(ii)-dependent metalloenzyme human carbonic anhydrase II (hCAII) by 19F NMR. The isomorphous replacement of Zn(ii) by Co(ii) in hCAII produces enhanced sensitivity and reveals the potential of 19F NMR-based techniques for metalloenzyme ligand discovery.
              Cover page: 19 F-Tagged metal binding pharmacophores for NMR screening of metalloenzymes
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2022)
              Metalloenzyme inhibitors typically share a common need to possess a metal-binding pharmacophore (MBP) for binding the active site metal ions. However, MBPs can suffer from physicochemical liabilities, impeding the pharmacological properties and drug-likeliness of inhibitors. To circumvent this, problematic features of the MBP can be identified and exchanged with isosteric replacements. Herein, the carboxylic and hydroxyl group of the salicylic acid MBP were replaced and a total of 27 salicylate metal-binding isosteres (MBIs) synthesized. Of these 27 MBIs, at least 12 represent previously unreported compounds, and the metal-binding abilities of >20 of the MBIs have not been previously reported. These salicylate MBIs were examined for their metal-binding features in model complexes, physicochemical properties, and biological activity. It was observed that salicylate MBIs can demonstrate a range of attractive physicochemical properties and bind to the metal in a variety of expected and unexpected binding modes. The biological activity of these novel MBIs was evaluated by measuring inhibition against two Zn2+-dependent metalloenzymes, human glyoxalase 1 (GLO1) and matrix metalloproteinase 3 (MMP-3), as well as a dinuclear Mn2+-dependent metalloenzyme, influenza H1N1 N-terminal endonuclease (PAN). It was observed that salicylate MBIs could maintain or improve enzyme inhibition and selectivity. To probe salicylate MBIs as fragments for fragment-based drug discovery (FBDD), an MBI that showed good inhibitory activity against GLO1 was derivatized and a rudimentary structure-activity relationship was developed. The resulting elaborated fragments showed GLO1 inhibition with low micromolar activity.
                Cover page: Salicylate metal-binding isosteres as fragments for metalloenzyme inhibition
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2024)
                Alcohol Use Disorder (AUD) is a significant public health issue in the United States. It affects millions of individuals and their families and contributes to substantial societal and economic burdens. Despite the availability of some pharmacological treatments, there is still a pressing need to develop more effective therapeutic strategies to address the diverse range of symptoms and challenges associated with AUD. Catechol-O-methyltransferase (COMT) inhibition recently emerged as a promising new approach to treating AUD due to its potential to improve cognitive effects commonly associated with AUD. Tolcapone, an FDA-approved COMT inhibitor, has shown some promise for treating AUD; however, its ability to decrease drinking in ethanol-dependent rats has not been well-established. In this study, we evaluated the effects of tolcapone on operant, oral ethanol self-administration in non-dependent and dependent rats, and in rats that self-administered oral saccharin. To induce dependence, rats underwent the chronic intermittent exposure to vapor model, and their drinking levels were assessed during acute withdrawal from ethanol. Our results demonstrated that tolcapone attenuated responding for ethanol in dependent rats only, without affecting self-administration in non-dependent rats or rats self-administering saccharin. Moreover, we found that tolcapone was differentially effective in different estrous phases in female rats. These findings suggest that COMT inhibition, specifically using tolcapone, may be a valuable pharmacotherapy for treating AUD, particularly in individuals who are physically dependent on alcohol. Further research is needed to elucidate the precise mechanisms underlying the observed effects and to assess the potential of COMT inhibitors in a broader population of individuals with AUD.
                  Cover page: Catechol-O-Methyltransferase inhibition and alcohol use disorder: Evaluating the efficacy of tolcapone in ethanol-dependent rats.
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