The exploitation of metal-binding pharmacophores (MBPs) for use in fragment-based drug discovery (FBDD) has proven effective for targeting metalloenzymes. However, these MBPs can still suffer from pharmacokinetic liabilities, such as metabolic instability, poor solubility, and low membrane permeability, which limit the usefulness of lead compounds and can undermine the development of such compounds into clinically effective therapeutics. To address these issues, isosteric replacements of MBPs have been developed, which transforms MBPs into metal-binding isosteres (MBIs) as alternative compounds for FBDD. As an example, picolinic acid MBIs have been reported and evaluated for their metal-binding ability (using bioinorganic model compounds), pharmacokinetic properties, and enzyme inhibitory behavior. However, the structural, electronic, and spectroscopic properties of these MBIs with different metal ions have not been characterized, which could further reveal the similarities and differences between MBIs and the parent MBPs. In this respect, picolinic acid, several picolinic acid MBIs, and 2,2’-bipyridine were compared using a bioinorganic model system, [M(TPA)(MBI)] (M = Ni<sup>2+</sup> and Co<sup>2+</sup>, TPA = tris(2-pyridylmethyl)amine). These complexes were characterized by X-ray crystallography, magnetic moment, NMR, IR, MS, and UV−vis spectroscopy. These results provide broader insights into the concept of MBIs and improve the application of MBIs in structural-based drug design for metalloenzymes.

Elucidating metal-ligand interactions of metal-binding isosteres

ACS Spring Meeting 2021

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