The Interaction of Metal Compounds with Protein Targets: New Tools in Medicinal Chemistry and Chemical Biology

Abstract

In cells and organisms, metal complexes can be specifically designed to interact with biomolecules and accordingly alter important biological processes. These interactions have been widely explored for targeting specific biological functions and diseases. In fact, several studies have demonstrated that inorganic chemistry offers significant diversity and versatility for the preparation of highly potent protein modulators (e.g., inhibitors). Moreover, both coordination and organometallic complexes featuring favorable chemico‐physical properties (e.g., luminescence) have proven to be well suited to image proteins and peptides in living cells by various methods. An inherent advantage of metal complexes is the accessibility of multiple oxidation states, and overall charge and geometries, which makes them attractive from the point of view of chemical design. However, these properties can become a disadvantage if not controlled and fine‐tuned in the biological application. In this review, we generally discuss the use of metal compounds, targeting proteins and/or peptides, in medicinal chemistry and chemical biology, and then focus on representative recent examples and applications. Furthermore, we highlight future challenges and attractive perspectives in the field, which may stimulate research and define new frontiers in bioinorganic chemistry.

Acetylcholinesterase and Aβ Aggregation Inhibition by Heterometallic Ruthenium(II)–Platinum(II) Polypyridyl Complexes

“…Development of metal compounds as potential agents capable of modifying and inhibiting Aβ aggregation is an emerging area in metal-based therapeutic drug design. − A recent pioneering study by Barnham et al on Aβ aggregation inhibition by covalent binding platinum complexes triggered new research, and several Pt, Ru, Rh, and Ir complexes have been developed, principally targeting Aβ aggregation and the Cu–Aβ redox process . These complexes are able to bind Aβ covalently, interfere with the Aβ–Cu redox process, inhibit Aβ aggregation, and/or act as luminescent Aβ sensors.…”

Computational simulations of Ru(II) complexes with coordinated jaborandi ligands and their potential for interaction with Trypanosoma cruzi proteases

“…In the search for new drugs, spectroscopic techniques, protein crystallography and theoretical computational methods have been applied to metallic species (SOLOMON; SCOTT; KING, 2009;SIGEL, 2014;MILLER et al, 2017), helping to understand the types of interactions carried out between metals, ligands and biomolecules, and the influence on the behavior of metallopharmaceuticals (REIS, 2021).…”

Gold(i) metallocyclophosphazenes with antibacterial potency and antitumor efficacy. Synergistic antibacterial action of a heterometallic gold and silver-cyclophosphazene

“…Since the discovery of cisplatin 1,2 as one of the most powerful chemotherapeutic agents against ovarian and testicular cancer, a vast library of metal complexes has been synthesized and applied in the pharmacological field, mostly as anticancer agents, but also as anti-inflammatory, antimicrobial, antirheumatic, and antimalarial drugs. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Among the non-platinum drugs, gold complexes have attracted major attention in inorganic medicinal chemistry and are gaining attention in all areas especially as anticancer agents. [18][19][20][21][22] Ever since the work of R. Koch in the 19th century, who demonstrated that K[Au(CN) 2 ] showed activity against Mycobacterium tuberculosis, a large number of gold complexes have been tested in vitro against a broad spectrum of bacteria, fungi and parasites.…”

“…Since the discovery of cisplatin 1,2 as one of the most powerful chemotherapeutic agents against ovarian and testicular cancer, a vast library of metal complexes has been synthesized and applied in the pharmacological field, mostly as anticancer agents, but also as anti-inflammatory, antimicrobial, antirheumatic, and antimalarial drugs. 3–17 Among the non-platinum drugs, gold complexes have attracted major attention in inorganic medicinal chemistry and are gaining attention in all areas especially as anticancer agents. 18–22…”