Study of the anticancer potential of Cd complexes of selenazoyl-hydrazones and their sulfur isosters.

The biological activity of Cd compounds has been investigated scarce since Cd has been recognized as a human carcinogen. However, the toxicity of cadmium is comparable to the toxicity of noble metals such as Pt and Pd. The paradigm of metal toxicity has been challenged suggesting that metal toxicity is not a constant property, yet it depends on many factors like the presence of appropriate ligands. Studies on anticancer activity of cadmium complexes showed that the complexation of various ligands resulted in complexes that showed better activities than approved drugs. In the present study, cadmium complexes with biologically potent thiazolyl/selenazoyl-hydrazone ligands have been prepared, and tested for their activity against different types of tumor cell models. The complexation of ligands with Cd(II) resulted in a synergistic effect. The antiproliferative activity study revealed that all complexes are more active compared to 5-fluorouracil and cisplatin. The mechanism of tumor cell growth inhibition reveal that selenium-based compounds induce cell death in T-47D (gland carcinoma) cells through apoptosis via caspase-3/7 activation. Additionally, their pro-apoptotic effect was stronger compared to etoposide and cisplatin. Nuclease activity, detected by gel electrophoresis, may be the possible mechanism of anticancer action of investigated complexes.

New insights into the catalytic mechanism of the SARS-CoV-2 main protease: an ONIOM QM/MM approach.

SARS-CoV-2 Mpro, also known as the main protease or 3C-like protease, is a key enzyme involved in the replication process of the virus that is causing the COVID-19 pandemic. It is also the most promising antiviral drug target targeting SARS-CoV-2 virus. In this work, the catalytic mechanism of Mpro was studied using the full model of the enzyme and a computational QM/MM methodology with a 69/72-atoms QM region treated at DLPNO-CCSD(T)/CBS//B3LYP/6-31G(d,p):AMBER level and including the catalytic important oxyanion-hole residues. The transition state of each step was fully characterized and described together with the related reactants and products. The rate-limiting step of the catalytic process is the hydrolysis of the thioester-enzyme adduct, and the calculated barrier closely agrees with the available kinetic data. The calculated Gibbs free energy profile, together with the full atomistic detail of the structures involved in catalysis, can now serve as valuable models for the rational drug design of transition state analogs as new inhibitors targeting the SARS-CoV-2 virus.

The milk-derived lactoferrin inhibits V-ATPase activity by targeting its V1 domain.

Lactoferrin (Lf), a bioactive milk protein, exhibits strong anticancer and antifungal activities. The search for Lf targets and mechanisms of action is of utmost importance to enhance its effective applications. A common feature among Lf-treated cancer and fungal cells is the inhibition of a proton pump called V-ATPase. Lf-driven V-ATPase inhibition leads to cytosolic acidification, ultimately causing cell death of cancer and fungal cells. Given that a detailed elucidation of how Lf and V-ATPase interact is still missing, herein we aimed to fill this gap by employing a five-stage computational approach. Molecular dynamics simulations of both proteins were performed to obtain a robust sampling of their conformational landscape, followed by clustering, which allowed retrieving representative structures, to then perform protein-protein docking. Subsequently, molecular dynamics simulations of the docked complexes and free binding energy calculations were carried out to evaluate the dynamic binding process and build a final ranking based on the binding affinities. Detailed atomist analysis of the top ranked complexes clearly indicates that Lf binds to the V1 cytosolic domain of V-ATPase. Particularly, our data suggest that Lf binds to the interfaces between A/B subunits, where the ATP hydrolysis occurs, thus inhibiting this process. The free energy decomposition analysis further identified key binding residues that will certainly aid in the rational design of follow-up experimental studies, hence bridging computational and experimental biochemistry.