Modeling Adsorption of CO2 in Rutile Metallic Oxide Surfaces: Implications in CO2 Catalysis.

CO2 is the most abundant greenhouse gas, and for this reason, it is the main target for finding solutions to climatic change. A strategy of environmental remediation is the transformation of CO2 to an aggregated value product to generate a carbon-neutral cycle. CO2 reduction is a great challenge because of the large C=O dissociation energy, ~179 kcal/mol. Heterogeneous photocatalysis is a strategy to address this issue, where the adsorption process is the fundamental step. The focus of this work is the role of adsorption in CO2 reduction by means of modeling the CO2 adsorption in rutile metallic oxides (TiO2, GeO2, SnO2, IrO2 and PbO2) using Density Functional Theory (DFT) and periodic DFT methods. The comparison of adsorption on different metal oxides forming the same type of crystal structure allowed us to observe the influence of the metal in the adsorption process. In the same way, we performed a comparison of the adsorption capability between two different surface planes, (001) and (110). Two CO2 configurations were observed, linear and folded: the folded conformations were observed in TiO2, GeO2 and SnO2, while the linear conformations were present in IrO2 and PbO2. The largest adsorption efficiency was displayed by the (001) surface planes. The CO2 linear and folded configurations were related to the interaction of the oxygen on the metallic surface with the adsorbate carbon, and the linear conformations were associated with the physisorption and folded configurations with chemisorption. TiO2 was the material with the best performance for CO2 interactions during the adsorption.

Grammatical evolution-based design of SARS-CoV-2 main protease inhibitors.

A series of SARS-CoV-2 main protease (SARS-CoV-2-Mpro) inhibitors were modeled using evolutive grammar algorithms. We have generated an automated program that finds the best candidate to inhibit the main protease, Mpro, of SARS-CoV-2. The candidates were constructed based on a pharmacophore model of the above-mentioned target; relevant moieties of such molecules were modified using data-basis sets with similar chemical behavior to the reference moieties. Additionally, we used the SMILES language to translate 3D chemical structures to 1D words; then, an evolutive grammar algorithm was used to explore the chemical space and obtain new candidates, which were evaluated via the binding energy of molecular coupling assays as an evaluation function. Finally, sixteen molecules were obtained in 3 runs of our program, three of which show promising binding properties as SARS-CoV-2-Mpro inhibitors. One of them, TTO, maintained its relevant binding properties during 100 ns molecular dynamics experiments. For this reason, TTO is the best candidate to inhibit SARS-CoV-2-Mpro. The software we developed for this contribution is available at the following URL: https://github.com/masotelof/GEMolecularDesign.

Design of Fluorescent Coumarin-Hydroxamic Acid Derivatives as Inhibitors of HDACs: Synthesis, Anti-Proliferative Evaluation and Docking Studies.

Coumarin-hydroxamic acid derivatives 7a-k were herein designed with a dual purpose: as antiproliferative agents and fluorescent probes. The compounds were synthesized in moderate yields (30-87%) through a simple methodology, biological evaluation was carried out on prostate (PC3) and breast cancer (BT-474 and MDA-MB-231) cell lines to determine the effects on cell proliferation and gene expression. For compounds 7c, 7e, 7f, 7i and 7j the inhibition of cancer cell proliferation was similar to that found with the reference compound at a comparable concentration (10 µM), in addition, their molecular docking studies performed on histone deacetylases 1, 6 and 8 showed strong binding to the respective active sites. In most cases, antiproliferative activity was accompanied by greater levels of cyclin-dependent kinase inhibitor p21, downregulation of the p53 tumor suppressor gene, and regulation of cyclin D1 gene expression. We conclude that compounds 7c, 7e, 7f, 7i and 7j may be considered as potential anticancer agents, considering their antiproliferative properties, their effect on the regulation of the genes, as well as their capacity to dock to the active sites. The fluorescent properties of compound 7j and 7k suggest that they can provide further insight into the mechanism of action.

Evaluation of doxorubicin and ß-lapachone analogs as anticancer agents, a biological and computational study.

We have conducted an experimental and computational evaluation of new doxorubicin (4a-c) and ß-lapachone (5a-c) analogs. These novel anticancer analogs were previously synthesized, but had not been tested or characterized until now. We have evaluated their antiproliferative and DNA cleavage inhibition properties using breast (MCF-7 and MDA-MB-231) and prostate (PC3) cancer cell lines. Additionally, cell cycle analysis was performed using flow cytometry. Computational studies, including molecular docking, pharmacokinetic properties, and an analysis of DFT and QTAIM chemical descriptors, were performed to gain insights into the electronic structure and elucidate the molecular binding of the new ß-lapachone and doxorubicin analogs with a DNA sequence and Topoisomerase II (Topo II)α. Our results show that 4a analog displays the highest antiproliferative activity in cancer cell lines by inducing cell death. We observed that stacking interactions and hydrogen bonding are essential to stabilize the molecule-DNA-Topo IIα complex. Moreover, 4a and 5a analogs inhibited Topo's DNA cleavage activity. Pharmacodynamic results indicated that studied molecules have favorable adsorption and permeability properties. The calculated chemical descriptors indicate that electron accumulation in quinone rings is relevant to the reactivity and biological activity. Based on our results, 4a is a strong candidate for becoming an anticancer drug.

Exploring novel capping framework: high substituent pyridine-hydroxamic acid derivatives as potential antiproliferative agents.

PURPOSE: Histone deacetylases (HDACs) play a vital role in the epigenetic regulation of gene expression due to their overexpression in several cancer forms. Therefore, these enzymes are considered as a potential anticancer drug target. Different synthetic and natural structures have been studied as HDACs inhibitors; based on available structural design information, the capping group is important for the biological activity due to the different interactions in the active site entrance. The present study aimed to analyze high substituted pyridine as a capping group, which included carrying out the synthesis, antiproliferative activity analysis, and docking studies of these novel compounds. METHODS: To achieve the synthesis of these derivatives, four reaction steps were performed, generating desired products 15a-k. Their effects on cell proliferation and gene expression of p21, cyclin D1, and p53 were determined using the sulphorhodamine B (SRB) method and quantitative real-time polymerase chain reaction. The HDAC1, HDAC6, and HDAC8 isoforms were used for performing docking experiments with our 15a-k products. RESULT: The products 15a-k were obtained in overall yields of 40-71%. Compounds 15j and 15k showed the highest antiproliferative activity in the breast (BT-474 and MDA-MB-231) and prostate (PC3) cancer cell lines at a concentration of 10 µM. These compounds increased p21 mRNA levels and decreased cyclin D1 and p53 gene expression. The docking study showed an increment in the strength, and in the number of interactions performed by the capping moiety of the tested molecules compared with SAHA; interactions displayed are mainly van der Waals, π-stacking, and hydrogen bond. CONCLUSION: The synthesized compounds 2-thiophene (15j) and 2-furan (15k) pyridine displayed cell growth inhibition, regulation of genes related to cell cycle progression in highly metastatic cancer cell lines. The molecular coupling analysis performed with HDAC1, HDAC6 and HDAC8 showed an increment in the number of interactions performed by the capping moiety and consequently in the strength of the capping group interaction.