Lessons from Nature: A Bio-Inspired Approach to Molecular Design

Abstract

Metalloproteins contain actives sites with intricate structures that perform specific functions with high selectivity and efficiency. The complexity of these systems complicates the study of their function and the understanding of the properties that give rise to their reactivity. One approach that has contributed to the current level of understanding of their biological function is the study of synthetic constructs that mimic one or more aspects of the native metalloproteins. These systems allow individual contributions to the structure and function to be analyzed and also permit spectroscopic characterization of the metal cofactors without complications from the protein environment. This Current Topics is a review of synthetic constructs as probes for understanding the biological activation of small molecules. These topics are developed from the perspective of seminal molecular design breakthroughs from the past that provide the foundation for the systems used today.

Manganese–Hydroxido Complexes Supported by a Urea/Phosphinic Amide Tripodal Ligand

“…Rather than using covalent bonds, the secondary coordination spheres of metal ions are regulated through networks of weaker non-covalent interactions that are often difficult to manipulate within synthetic systems. 5,6 Hydrogen bonds (H-bonds) are the most versatile of these interactions and have been actively designed into a variety of ligand frameworks. The most common of these ligands incorporate either H-bond donors or acceptors to promote intramolecular H-bonds.…”

Effect of donor atom identity on metal-binding pharmacophore coordination

“…Despite major advances in their development in mimicking the coordinating residues and the first coordination sphere of an active site [15], model complexes still struggle to mimic the nuanced details of the second coordination sphere of a metalloenzyme active site. These key second coordination sphere interactions, which are usually absent in model complexes, can have a significant impact on inhibitor binding and selectivity and should not be neglected.…”

De Novo Design of an Allosteric Metalloprotein Assembly with Strained Disulfide Bonds

“…This stands in contrast to most examples in molecular design where metal coordination and reactivity are exclusively handled at the primary and secondary coordination spheres. 6, 9 Second, the increased strain has allowed metal coordination to be directly and remotely linked to the formation/breakage of a distinct disulfide bond within the quaternary scaffold, thereby creating an allosteric system. Individually, metal coordination and disulfide bond formation are commonly employed as allosteric effectors in biological systems.…”