Interaction between Proteins and Ir Based CO Releasing Molecules: Mechanism of Adduct Formation and CO Release

Abstract

Carbon monoxide releasing molecules (CORMs) have important bactericidal, anti-inflammatory, neuroprotective, and antiapoptotic effects and can be used as tools for CO physiology experiments, including studies on vasodilation. In this context, a new class of CO releasing molecules, based on pentachlorocarbonyliridate(III) derivative have been recently reported. Although there is a growing interest in the characterization of protein-CORMs interactions, only limited structural information on CORM binding to protein and CO release has been available to date. Here, we report six different crystal structures describing events ranging from CORM entrance into the protein crystal up to the CO release and a biophysical characterization by isothermal titration calorimetry, Raman microspectroscopy, and molecular dynamics simulations of the complex between a pentachlorocarbonyliridate(III) derivative and hen egg white lysozyme, a model protein. Altogether, the data indicate the formation of a complex in which the ligand can bind to different sites of the protein surface and provide clues on the mechanism of adduct formation and CO release.

Improving the Anti-inflammatory Response via Gold Nanoparticle Vectorization of CO-Releasing Molecules

“…In the last 2 decades, different molecules have been designed as CORMs, particularly transitional metal carbonyl complexes, which contain a heavy metal surrounded by carbonyl (CO) groups as the coordinated ligand . A great variety of metals have been tested, including ruthenium, molybdenum, and iridium. − However, nonmetal-based CORMs have also been developed . Both metal and nonmetal-based CORMs possess alternative trigger mechanisms responsible for the CO release. , The design of CORMs that is able to release the CO site specifically has been a big challenge since their inception: the first CORMs were hardly water soluble, and the release of CO was too fast. , Soon after, Motterlini and co-workers developed the water-soluble metal complex tricarbonylchloro­(glycinato)­ruthenium­(II) (CORM-3), which exhibits an anti-inflammatory action in vivo as well as renoprotective and antiapoptotic effects. − However, despite the potential beneficial effects, the clinical application of CORM-3 is limited due to the lack of suitable drug-like properties, namely, its reduced CO release half-time and poor stability in aqueous media …”

An NMR-Guided Screening Method for Selective Fragment Docking and Synthesis of a Warhead Inhibitor

“…The initial strategy was to couple a ruthenium piano-stool compound derived from benzylamine to RK207, generating an organometallic-based lead compound. Ru-containing compounds have been popular in anti-cancer and antibiotic therapeutic design, as reviewed recently [37,38]. These compounds also tend to interact with soft nucleophilic centers in proteins, such as the thiolates present in GRX active sites [39].…”

Enzyme Crystals and Hydrogel Composite Membranes as New Active Food Packaging Material

“…The XDS program was used to perform data reduction, while POINTLESS and AIMLESS programs were used to find the space group symmetry and scale the diffraction data. The structure was solved by molecular replacement (MR), using the REMO program included in the package ILMILIONE with the crystal structure 4N9R as MR model. The matching between experimental and calculated electron densities was improved by performing an automatic building procedure on the structure obtained by MR in “rebuilt‐in‐place” mode, by using Autobuild wizard included in PHENIX …”