Interaction of copper potential metallodrugs with TMPRSS2: A comparative study of docking tools and its implications on COVID-19.

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. For the virus to enter the host cell, its spike (S) protein binds to the ACE2 receptor, and the transmembrane protease serine 2 (TMPRSS2) cleaves the binding for the fusion. As part of the research on COVID-19 treatments, several Casiopeina-analogs presented here were looked at as TMPRSS2 inhibitors. Using the DFT and conceptual-DFT methods, it was found that the global reactivity indices of the optimized molecular structures of the inhibitors could be used to predict their pharmacological activity. In addition, molecular docking programs (AutoDock4, Molegro Virtual Docker, and GOLD) were used to find the best potential inhibitors by looking at how they interact with key amino acid residues (His296, Asp 345, and Ser441) in the catalytic triad. The results show that in many cases, at least one of the amino acids in the triad is involved in the interaction. In the best cases, Asp435 interacts with the terminal nitrogen atoms of the side chains in a similar way to inhibitors such as nafamostat, camostat, and gabexate. Since the copper compounds localize just above the catalytic triad, they could stop substrates from getting into it. The binding energies are in the range of other synthetic drugs already on the market. Because serine protease could be an excellent target to stop the virus from getting inside the cell, the analyzed complexes are an excellent place to start looking for new drugs to treat COVID-19.

Tris(2-Pyridylmethylamine)V(O)2 Complexes as Counter Ions of Diprotonated Decavanadate Anion: Potential Antineoplastic Activity.

The synthesis and theoretical-experimental characterization of a novel diprotanated decavanadate is presented here due to our search for novel anticancer metallodrugs. Tris(2-pyridylmethyl)amine (TPMA), which is also known to have anticancer activity in osteosarcoma cell lines, was introduced as a possible cationic species that could act as a counterpart for the decavanadate anion. However, the isolated compound contains the previously reported vanadium (V) dioxido-tpma moieties, and the decavanadate anion appears to be diprotonated. The structural characterization of the compound was performed by infrared spectroscopy and single-crystal X-ray diffraction. In addition, DFT calculations were used to analyze the reactive sites involved in the donor-acceptor interactions from the molecular electrostatic potential maps. The level of theory mPW1PW91/6-31G(d)-LANL2DZ and ECP = LANL2DZ for the V atom was used. These insights about the compounds' main interactions were supported by analyzing the noncovalent interactions utilizing the AIM and Hirshfeld surfaces approach. Molecular docking studies with small RNA fragments were used to assess the hypothesis that decavanadate's anticancer activity could be attributed to its interaction with lncRNA molecules. Thus, a combination of three potentially beneficial components could be evaluated in various cancer cell lines.

Synthesis, Crystal Structure, and Computational Methods of Vanadium and Copper Compounds as Potential Drugs for Cancer Treatment.

Transition metal-based compounds have shown promising uses as therapeutic agents. Among their unique characteristics, these compounds are suitable for interaction with specific biological targets, making them important potential drugs to treat various diseases. Copper compounds, of which Casiopeinas® are an excellent example, have shown promising results as alternatives to current cancer therapies, in part because of their intercalative properties with DNA. Vanadium compounds have been extensively studied for their pharmacological properties and application, mostly in diabetes, although recently, there is a growing interest in testing their activity as anti-cancer agents. In the present work, two compounds, [Cu(Metf)(bipy)Cl]Cl·2H2O and [Cu(Impy)(Gly)(H2O)]VO3, were obtained and characterized by visible and FTIR spectroscopies, single-crystal X-ray diffraction, and theoretical methods. The structural and electronic properties of the compounds were calculated through the density functional theory (DFT) using the Austin-Frisch-Petersson functional with dispersion APFD, and the 6-311 + G(2d,p) basis set. Non-covalent interactions were analyzed using Hirshfeld surface analysis (HSA) and atom in molecules analysis (AIM). Additionally, docking analysis to test DNA/RNA interactions with the Casiopeina-like complexes were carried out. The compounds provide metals that can interact with critical biological targets. In addition, they show interesting non-covalent interactions that are responsible for their supramolecular arrangements.

Cyclo-tetravanadate bridged copper complexes as potential double bullet pro-metallodrugs for cancer treatment.

Over the last decade, copper and vanadium complexes have shown promising properties for the treatment of several types of cancer. In particular, Casiopeinas®, a group of copper-based complexes, has received specific attention, and their mechanism of action has been extensively studied since their structure is simple and their synthesis may be affordable. Similarly, vanadium-containing compounds in the form of complexes and simple polyoxovanadates have also been studied as antitumor agents. Here, potential prodrugs that would release the two metals, V and Cu, in usable form to act in conjunction against cancer cells are reported. The new series of Casiopeinas-like compounds are bridged by a cyclotetravanadate ion with the generic formula [Cu(N,N')(AA)]2•(V4O12), where (N,N') represent 1,10-phenanthroline and 2,2'-bipyridine, and (AA) are aminoacidate ions (Lysine and Ornithine). The compounds were characterized by elemental analysis, single-crystal X-ray diffraction and Visible, FTIR, and Raman spectroscopies, as well as 51V NMR, EPR, and Thermogravimetric Analysis. Additionally, theoretical calculations based on the Density Functional Theory (DFT) were carried out to model the compounds. Optimized structures, theoretical IR, and Raman spectra were also obtained, as well as docking analysis to test DNA interactions with the casiopeina-like complexes. The compounds may act as prodrugs by providing acting molecules that have showed potential pharmacological properties for the treatment of several types of cancer.

Oxidovanadium(V) complexes as promising anticancer photosensitizers.

Photodynamic therapy (PDT) is an alternative treatment widely used against cancer. PDT requires molecular systems, known as photosensitizers (PS), which not only exhibit strong absorption at a particular wavelength range, but also need to be selectively accumulated inside cancer cells. PS are activated by specific wavelengths that cause tumor cell death by mechanisms related with oxidative stress. In this paper, three oxidovanadium(V) complexes linked to a Schiff base, which exhibit anticancer activity by displaying desirable accumulation inside malignant cells, are studied using Density Functional Theory (DFT) and Time Dependent-DFT (TD-DFT) methodologies to characterize their structural and photophysical properties as possible PS. The maximum absorption of these complexes in aqueous solution was predicted to be approximately 460 nm presenting a ligand-to-metal charge transfer. Additionally, we describe the photodynamic type reaction that these complexes can undergo when considered as PS candidates. Our results suggest that the system, containing triethylammonium as substituent, is the most suitable complex to act both as PS and as a possible therapeutic candidate in PDT.

Inhibitory mechanism of 17ß-aminoestrogens in the formation of Aß aggregates.

Alzheimer's disease (AD) is a complex neurodegenerative disorder associated with the aggregation of the amyloid-beta peptide (Aß) into large oligomers and fibrils that damage healthy brain cells. The predominant peptide fragments in the plaques are mainly formed by the Aß1-40 and Aß1-42 peptides, albeit the eleven-residue Aß25-35 segment is largely used in biological studies because it retains the neurotoxic properties of the longer Aß peptides. Recent studies indicate that treatment with therapeutic steroid hormones reduces the progress of the disease in AD models. Particularly, treatment with 17ß-aminoestrogens (AEs) has shown a significant alleviation of the AD development by inhibiting oxidative stress and neuronal death. Yet, the mechanism by which the AE molecules exhibit their beneficial effects remains speculative. To shed light into the molecular mechanism of inhibition of the AD development by AEs, we investigated the possibility of direct interaction with the Aß25-35 peptide. First, we calculate various interacting electronic properties of three AE derivatives as follows: prolame, butolame, and pentolame by performing DFT calculations. To account for the polymorphic nature of the Aß aggregates, we considered four different Aß25-35 systems extracted from AD relevant fibril structures. From the calculation of different electron density properties, specific interacting loci were identified that guided the construction and optimization of various complexes. Interestingly, the results suggest a similar inhibitory mechanism based on the direct interaction between the AEs and the M35 residue that seems to be general and independent of the polymorphic properties of the Aß aggregates. Our analysis of the complex formation provides a structural framework for understanding the AE therapeutic properties in the molecular inhibitory mechanism of Aß aggregation.