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Exploring and Expanding the Coordination Chemistry of Metal-Binding Pharmacophores for Metalloenzyme Inhibition

  • Author(s): Dick, Benjamin
  • Advisor(s): Cohen, Seth M
  • et al.

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.

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