👤 S Bonnet

Despite the proven potential of metal complexes as therapeutics, the lack of computational tools available for the high-throughput screening of their interactions with proteins is a limiting factor toward clinical developments. To address this challenge, we introduce MetalDock, an easy-to-use, open access docking software for docking metal complexes to proteins. Our tool integrates the AutoDock docking engine with three well-known quantum software packages to automate the docking of metal-organic complexes to proteins. We used a Monte Carlo sampling scheme to obtain the missing Lennard-Jones parameters for 12 metal atom types and demonstrated that these parameters generalize exceptionally well. Our results show that the poses obtained by MetalDock are highly accurate, as they predict the binding geometries experimentally determined by crystal structures with high spatial reproducibility. Three different case studies are presented that demonstrate the versatility of MetalDock for the docking of diverse metal-organic compounds to different biomacromolecules, including nucleic acids. Show less

Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side effects. Much effort has been made to circumvent the drug resistance and general toxicity of these drugs. Among multifarious designs, monofunctional platinum(II) complexes with a general formula of [Pt(3A)Cl] + (A: Ammonia or amine) stand out as a class of “non-traditional” anticancer agents hopeful to overcome the defects of current platinum drugs. This review aims to summarize the development of monofunctional platinum(II) complexes in recent years. They are classified into four categories: fluorescent complexes, photoactive complexes, targeted complexes, and miscellaneous complexes. The intention behind the designs is either to visualize the cellular distribution, or to reduce the side effects, or to improve the tumor selectivity, or inhibit the cancer cells through non-DNA targets. The information provided by this review may inspire researchers to conceive more innovative complexes with potent efficacy to shake off the drawbacks of platinum anticancer drugs. Show less

In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H₂biqbpy1 and H₂biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au(biqbpy2)Cl ([2]Cl). In [1]⁺, two pyridyl rings coordinate to the metal via a Au-C bond (C^∧N^∧N^∧C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2]⁺ all four pyridyl rings of the ligand coordinate to the metal via a Au-N bond (N^∧N^∧N^∧N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [³H]dofetilide equally well from cell membranes expressing the K_v11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H₂biqbpy1 and H₂biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H₂biqbpy2 and TrxR-inhibiting Au⁺ ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au⁺ ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells. Show less

Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca 2+ signaling in cell and tissue homeostasis. Whether mitochondrial Ca 2+ uptake can be exploited as a weapon to counteract cancer progression is debated. In this review, we summarize recent research on the molecular structure of the MCU, the regulatory mechanisms that control its activity and its relevance in pathophysiology, focusing in particular on its role in cancer progression. Show less