Dennis Riley

Structure–Activity Studies and the Design of Synthetic Superoxide Dismutase (SOD) Mimetics as Therapeutics

Publisher Summary This chapter describes highly stable Mn(II) complexes that possess high superoxide dismutase (SOD) activity—the two key attributes for an efficient SOD mimetic-based drug. Key to success in designing and synthesizing highly stable and highly active SOD mimetics is the development of a detailed understanding of the mechanism of action of this class of SOD mimetics, and the subsequent development of a computer-aided design (CAD) paradigm based on molecular mechanics (MM) that makes it possible to study and screen a large number of possible structures prior to embarking on complicated syntheses of highly substituted and constrained ligands. An understanding of the details of the mechanism of action of synthetic superoxide dismutase catalysts has made it possible to devise a computer modeling paradigm that allows one to design highly substituted (and hence highly stable) complexes that possess high catalytic activity. Molecular mechanics calculations have made it possible to correctly predict how substituents and their stereochemistry affect the energetics of ligand folding and thus catalytic activity. The chemistry presented for designing and synthesizing core catalyst structures optimized for stability and catalytic activity, are amenable to the construction of complexes that have pendant functionality; for example, alcohols, amines, amides, esters, acids, etc.

Engineering metal complexes of chiral pentaazacrowns as privileged reverse-turn scaffolds.

Reverse turns are common structural motifs and recognition sites in protein/protein interactions. The design of peptidomimetics is often based on replacing the amide backbone of peptides by a non‐peptidic scaffold while retaining the biologic mode of action. This study evaluates the potential of metal complexes of chiral pentaazacrowns conceptually derived by reduction of cyclic pentapeptides as reverse‐turn mimetics. The possible conformations of metal complexes of chiral pentaazacrown scaffolds have been probed by analysis of 28 crystal structures complexed with six different metals (Mn, Fe, Co, Ni, Cu, and Zn). The solvated structures as well as the impact of complexation with different metals/oxidation states have been examined with density functional theory (DFT) calculation as explicitly represented by interactions with a single water molecule. The results suggest that most reverse‐turn motifs seen in proteins could be mimicked effectively with a subset of metal complexes of chiral pentaazacrown scaffolds with an RMSD of approximately 0.3 Å. Due to the relatively fixed orientation of the pendant chiral side groups in these metal complexes, one can potentially elicit information about the receptor‐bound conformation of the parent peptide from their binding affinities. The presence of 20 H‐atoms on the pentaazacrown ring that could be functionalized as well as the conformational perturbations available from complexation with different metals offer a desirable diversity to probe receptors for reverse‐turn recognition.