A Computational Method for the Binding Mode Prediction of COX-1 and COX-2 Inhibitors: Analyzing the Union of Coxibs, Oxicams, Propionic and Acetic Acids.

Among the biological targets extensively investigated to improve inflammation and chronic inflammatory conditions, cyclooxygenase enzymes (COXs) occupy a prominent position. The inhibition of these enzymes, essential for mitigating inflammatory processes, is chiefly achieved through Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). In this work, we introduce a novel method-based on computational molecular docking-that could aid in the structure-based design of new compounds or the description of the anti-inflammatory activity of already-tested compounds. For this, we used eight crystal complexes (four COX-1 and COX-2 each), and each pair had a specific NSAID: Celecoxib, Meloxicam, Ibuprofen, and Indomethacin. This selection was based on the ligand selectivity towards COX-1 or COX-2 and their binding mode. An interaction profile of each NSAID was compiled to detect the residues that are key for their binding mode, highlighting the interaction made by the Me group. Furthermore, we rigorously validated our models based on structural accuracy (RMSD < 1) and (R2 > 70) using eight NSAIDs and thirteen compounds with IC50 values for each enzyme. Therefore, this model can be used for the binding mode prediction of small and structurally rigid compounds that work as COX inhibitors or the prediction of new compounds that are designed by means of a structure-based approach.

On the energetic and magnetic stability of neutral and charged lithium clusters doped with one and two yttrium atoms.

DFT calculations were performed to study the effect on energetic and magnetic stability when clusters with up to 24 lithium atoms were doped with one and two atoms of yttrium. In this, the effect of the charge was considered. As a result, some stable structures were identified as possible magnetic superatoms, among them, the YLi12+ cluster with an icosahedron geometry with a spin magnetic moment of 4 bohr magnetons. The participation of yttrium in the electron density of the unpaired electrons providing magnetism in clusters was corroborated at the level of a density of states (DOS) calculation and a spin density calculation. In particular, in the Y2Li12+ superatom, it was found that the encapsulated yttrium atom participates with 35.02% and the second yttrium atom with 15.04%. These percentages, with a contribution from p orbitals, but to a greater extent by d orbitals. The complementation to these percentages is due to the participation of the s and p orbitals of the lithium atoms. In general, doping with a second yttrium atom allowed to obtain a greater amount of high magnetic moments, and considering charged clusters allowed to obtain also high magnetic moments.

Tamoxifen Sensitizes Acute Lymphoblastic Leukemia Cells to Cannabidiol by Targeting Cyclophilin-D and Altering Mitochondrial Ca2+ Homeostasis.

Cytotoxic effects of cannabidiol (CBD) and tamoxifen (TAM) have been observed in several cancer types. We have recently shown that CBD primarily targets mitochondria, inducing a stable mitochondrial permeability transition pore (mPTP) and, consequently, the death of acute lymphoblastic leukemia (T-ALL) cells. Mitochondria have also been documented among cellular targets for the TAM action. In the present study we have demonstrated a synergistic cytotoxic effect of TAM and CBD against T-ALL cells. By measuring the mitochondrial membrane potential (ΔΨm), mitochondrial calcium ([Ca2+]m) and protein-ligand docking analysis we determined that TAM targets cyclophilin D (CypD) to inhibit mPTP formation. This results in a sustained [Ca2+]m overload upon the consequent CBD administration. Thus, TAM acting on CypD sensitizes T-ALL to mitocans such as CBD by altering the mitochondrial Ca2+ homeostasis.

Magnesium oxide clusters as promising candidates for hydrogen storage.

With the idea of proposing solid state systems that have a high storage capacity of molecular hydrogen, a density functional theory study of magnesium oxide (MgO)n clusters (n = 1-10) was carried out. Hydrogen-magnesium oxide systems presented adsorption energy values in accordance with the previously reported studies of physisorption processes; additionally negative values of ΔGads were found describing adsorption as a favorable process. Here, the (MgO)7 cluster presented the highest adsorption energy. The storage capacity by weight of the magnesium oxide clusters was greater than the recommended percentage (7.5%) by the U.S. Department of Energy. QTAIM analysis and non-covalent index plots highlighted the weak nature of the interaction between the MgO clusters and hydrogen molecules, and the fundamental role of the Mg-O bonds' polarity in the systems' storage capacity.

In silico structure-based design of GABAB receptor agonists using a combination of docking and QSAR.

The study of γ-aminobutyric acid B receptor (GABAB ) activation is of great interest for several brain disorders. The search of new GABAB receptor agonists has been carried out by many research groups. As a result, Baclofen has become the prototypical GABAB receptor agonist. However, several attempts have been made to modify its structure to generate derivatives with improved activity. In this work, we carried out a theoretical and computational study for a wide range of GABAB receptor agonists reported in the literature. Molecular docking and QSAR techniques were combined by using the interaction energies of the agonists with the key residues of GABAB receptor, as molecular descriptors for the QSAR construction. The resulting mathematical model suggests that the activity of GABAB receptor agonists is influenced by three factors: their shape and molecular size (PW5 and PJI2), their constitutional features (ELUMO and T(N…O)) and the energy interaction with GABAB receptor (ETRP278 ). This model was validated by the QUIK, REDUNDANCY and OVERFITTING rules, and its predicted ability was tasted by the QLOO , QASYM , R02 and rm2 rules. Finally, six new compounds are proposed (35-40) with high potential to be used as GABAB receptor agonists.

Cytotoxic Acetogenins from the Roots of Annona purpurea.

Annona purpurea, known in Mexico as "cabeza de negro" or "ilama", belongs to the Annonaceae family. Its roots are employed in folk medicine in several regions of Mexico. Taking that information into account, a chemical and biological analysis of the components present in the roots of this species was proposed. Our results demonstrated that the dichloromethane (DCM) extract was exclusively constituted by a mixture of five new acetogenins named annopurpuricins A-E (1-5). These compounds have an aliphatic chain of 37 carbons with a terminal α,ß unsaturated γ-lactone. Compounds 1 and 2 belong to the adjacent bis-THF (tetrahydrofuran) α-monohydroxylated type, while compounds 3 and 4 belong to the adjacent bis-THF α,α'-dihydroxylated type; only compound 5 possesses a bis-epoxide system. Complete structure analysis was carried out by spectroscopy and chemical methods. All compounds were evaluated for their antiproliferative activity on three human tumor cell lines (MSTO-211H, HeLa and HepG2). Compounds 1-4 inhibited significantly the growth of HeLa and HepG2 cells, showing GI50 values in the low/subnanomolar range, while 5 was completely ineffective under the tested conditions. The investigation of the mechanism of action responsible for cytotoxicity revealed for the most interesting compound 1 the ability to block the complex I activity on isolated rat liver mitochondria (RLM).

Exploring the Structure, Energetic, and Magnetic Properties of Neutral Small Lithium Clusters Doped with Yttrium: Supermagnetic Atom Research.

Density functional theory calculations based on magnetic and energetic stability criteria were performed to study a series of yttrium-doped lithium neutral clusters. A relativistic approximation was employed to properly describe the energy and multiplicity of the given clusters' fundamental states. The interaction of the 4d-Y atomic orbitals with the sp-Li states had an important role in the magnetic and energetic behavior of the selected systems. The spin density was concentrated over the yttrium atom regardless of the size of the cluster. Li7Y is a new stable superatom due to its enhanced magnetic properties.

Silicon containing ibuprofen derivatives with antioxidant and anti-inflammatory activities: An in vivo and in silico study.

There are many chronic diseases related with inflammation. The chronic inflammation can produce other problems as cancer. Therefore, it is necessary to design drugs with better anti-inflammatory activity than those in the clinic. Likewise, these could be used in chronic treatments with minimum adverse effects. The amide or ester functionality in combination with the insertion of a silyl alkyl moiety is able to improve some drug properties. In this context, the evaluation of a group of silicon containing ibuprofen derivatives (SCIDs) as antioxidants and anti-inflammatory agents is reported. Antioxidant activity was evaluated by the 2,2-Diphenyl-1-picrylhydrazyl (DPPH⨪), 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS•+) and the Fe(II) chelating ability methods. The anti-inflammatory activity was determined by using the carrageenan induced rat paw edema. The gastrotoxic profile of the SCIDs that displayed significant anti-inflammatory activity was determined by the indomethacin induced ulceration method. The SCIDs performed better than ibuprofen as chelating agents for Fe(II) and as scavengers for the free radicals DPPH• and ABTS•+. On the anti-inflammatory test, compound 4a inhibited the edema up to 87%, while 4d &10b achieved significant inflammation inhibition at a lower effective dose 50 (ED50) than ibuprofen´s. None of the SCIDs endowed with anti-inflammatory activity, showed significant gastrotoxic effects with respect to those displayed by ibuprofen. Based on the experimental results and aided by the theoretical docking approach, it was possible to rationalize how the SCIDs may bind to cyclooxygenase isoforms and helped to explain their reduced gastrotoxicity. The evaluated effects were improved in SCIDs with respect to ibuprofen.

Lactobacillus plantarum WCFS1 ß-Fructosidase: Evidence for an Open Funnel-Like Channel Through the Catalytic Domain with Importance for the Substrate Selectivity.

ß-Fructosidase, a glycoside hydrolase of a biotechnologically important strain, was studied for its biochemical, physicochemical, and three-dimensional structure characteristics. This enzyme was heterologously expressed in Escherichia coli as a C-terminal His-tagged protein (SacB). ß-Fructosidase catalyzes the cleavage of glycoside bonds toward certain carbohydrates with ß-fructofuranosyl linkages; however, SacB exhibited selectivity toward sucrose and an optimum activity at pH 6.0-6.5 and 37 °C. In such optimum enzymatic activity conditions, the SacB was commonly observed as a monodisperse protein by dynamic light scattering (DLS). As ß-fructosidase belongs to glycoside hydrolase family 32 (GH32), a ß-sandwich and a five-bladed ß-propeller domain are typical predicted folds in its structure. Docking and molecular dynamic simulations revealed for the first time a funnel-like channel perfectly exposed in the ß-propeller domain of the Lactobacillus plantarum ß-fructosidase (this allows the interaction between its entire catalytic triad and substrates that are larger than sucrose). In contrast, SacB showed a closed central tunnel collaterally induced by its His-tag.

Evaluation of the antiradical activity of hyperjovinol-A utilizing donor-acceptor maps.

Hyperjovinol-A ((2-methyl-1-(2,4,6-trihydroxy-3-(3-hydroxy-3,7-dimethyloct-6-enyl)phen yl)propan-1-one) is an acylated phloroglucinol isolated from Hypericum Jovis and exhibiting good antioxidant activity. The study investigates the compound's antiradical ability on the basis of the electron-donor and electron-acceptor abilities of its conformers, deriving donor and acceptor indexes and mapping them in terms of donor-acceptor maps (DAM). The DAMs of vitamins C and E and of carotene astaxantine are used as comparison references. Calculations were performed at the DFT/BPW91/6-311+G(d,p) level, with optimizations on fully relaxed geometries to obtain the conformers of the neutral molecule in vacuo, and single point calculations to obtain the energies of the cationic and anionic species in vacuo and of the neutral, cationic, and anionic species in water, ethanol, and pentylethanoate. The calculations in solution utilized the polarizable continuum model (PCM). The results indicate that hyperjovinol-A may have better antiradical activity than vitamin C. This is in agreement with experimental results, showing that the antioxidant activity of hyperjovinol-A is comparable with that of the best drugs currently in clinical use. The activity is maintained in solution. The Fukui function f(·) was also calculated for all the conformers of hyperjovinol-A, to identify the regions of highest reactivity.

Synthesis and in vitro antioxidant activity evaluation of 3-carboxycoumarin derivatives and QSAR study of their DPPH• radical scavenging activity.

The in vitro antioxidant activities of eight 3-carboxycoumarin derivatives were assayed by the quantitative 1,1-diphenyl-2-picrylhydrazil (DPPH•) radical scavenging activity method. 3-Acetyl-6-hydroxy-2H-1-benzopyran-2-one (C1) and ethyl 6-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate (C2) presented the best radical-scavenging activity. A quantitative structure-activity relationship (QSAR) study was performed and correlated with the experimental DPPH• scavenging data. We used structural, geometrical, topological and quantum-chemical descriptors selected with Genetic Algorithms in order to determine which of these parameters are responsible of the observed DPPH• radical scavenging activity. We constructed a back propagation neural network with the hydrophilic factor (Hy) descriptor to generate an adequate architecture of neurons for the system description. The mathematical model showed a multiple determination coefficient of 0.9196 and a root mean squared error of 0.0851. Our results shows that the presence of hydroxyl groups on the ring structure of 3-carboxy-coumarins are correlated with the observed DPPH• radical scavenging activity effects.

Renin gene haplotype diversity and linkage disequilibrium in two Mexican and one German population samples.

INTRODUCTION: Renin is the main rate-limiting enzyme in the renin-angiotensin-aldosterone system. Its gene, REN, is a candidate crucial factor in essential hypertension and cardiovascular disease. The aim of this study was to evaluate allele and haplotype distributions of REN polymorphisms, and to estimate normalised linkage disequilibrium (D') in Mexican and German populations. MATERIALS AND METHODS: Four groups were studied for the REN single nucleotide polymorphisms (SNPs) 1205C>T, 1303G>A, and 10607G>A, in population samples of Mexican Mestizo (n = 86), Mexican Huichol (n = 49), German (n = 39), and individuals with hypertension diagnosis (n = 66). Polymorphisms were detected by PCR-RFLP. Genotype, allele and haplotype frequencies were estimated. RESULTS: SNP 1205C>T and 10607G>A allele and genotype distribution showed inter-group differences. The 1205T and 10607A allele showed a significance difference in hypertensive population. Haplotype analysis also showed some inter-group differences, especially in 1205C-1303G-10607G, 1205C-1303G-10607A and 1205T-1303G-10607G haplotypes. The segregation analysis disclosed complete linkage disequilibrium between 1205 and 1303 loci. CONCLUSION: These results provide an example of genetic diversity in related populations and illustrate the convenience of increasing the number of loci in associative studies between diseases and candidate genes.

A helicoid ferrocene.

Here, we address the problem of stabilizing a new helicoid ferrocene. Of course, to obtain a helical complex, it is essential to design suitable organic ligands. The ligands should possess the correct symmetry to match the geometrical requirement of the metal center. We propose in silico a beautiful helix that consists of one polycyclic hydrocarbon composed of 10 fused cyclopentadiene rings bound on opposite sides of an iron atom. The nature of the metal-ligand interactions between Fe(2+) and the ligand was investigated with energy decomposition analysis. Our results provide strong evidence for the viability of the hitherto unknown helicoid ferrocene as a target for synthesis.

Density Functional Study of the Structure and Properties of Cu9 and Cu9(-) .

This work presents a study of the structure of neutral and anionic copper cluster nonamers with density functional theory calculations. The structure optimization and frequency analysis were performed at the local density approximation (LDA) level of theory with the exchange correlation functional by Vosko, Wilk, and Nusair (VWN). Improved calculations for the structure stability were based on the generalized gradient approximation (GGA) where the exchange correlation functional of Perdew and Wang (PW) was used. For both neutral and anionic clusters, new isomers are found that are more stable than those already presented in the literature. Adiabatic and vertical electron affinities are calculated and compared with the experimental value reported for Cu9. The calculated values are in good agreement with the available experimental data. An analysis of the most relevant molecular orbitals (MOs) of the low-lying neutral and anionic copper cluster nonamers is reported, too.

2-[(R-phenyl)amine]-1,4-naphthalendiones as photosystem I electron acceptors: structure-activity relationship of m- and p-PAN compounds with QSAR analysis.

Nineteen 2-[(R-phenyl)amine]-1,4-naphthalendione derivatives (PAN) were tested on spinach thylakoids for their activity as electron acceptors. These molecules act as photosystem I electron acceptors in the micromolar range. AC(50) values varied from 5 nM to 24 microM. QSAR analysis revealed a linear correlation of the m-PAN derivative log [1/AC(50)] with the energy difference of the LUMO and HOMO orbitals. The biological activity of p-PAN derivatives correlates linearly with structural parameters. Electron affinity is being the most important. The half wave I potential values (E(1/2)) of PAN compounds (from -213 to -569 mV vs. NHE) match with the mid-point potentials of the A(0) to F(X) niche of PSI electron transport carriers. The logP values of PAN derivatives were 3.35 and 3.88, indicating that they are hydrophobic compounds. Therefore PAN compounds accept electrons at the hydrophobic A(0) to F(X) niche of PSI.

Separation of sigma and pi energies.

This work presents an all-electron density functional theory implementation of the separation of sigma and pi energies. On the basis of the separation of the electronic density, rho, into sigma and pi parts, an ansatz for the separation of the exchange-correlation energy is proposed. The behavior of the sigma and pi energy parts in benzene is investigated under different distortions. The effect of local and nonlocal functionals on the separation of the exchange-correlation energy is studied, too.