QSAR Modelling of Biological Activity in Cannabinoids with Quantum Similarity Combinations of Charge Fitting Schemes and 3D-QSAR.

Quantitative structure-activity relationship(QSAR) modeled the biological activities of 30 cannabinoids with quantum similarity descriptors(QSD) and Comparative Molecular Field Analysis (CoMFA). The PubChem[https://pubchem.ncbi.nlm.nih.gov/] database provided the geometries, binding affinities(Ki ) to the cannabinoid receptors type 1(CB1) and 2(CB2), and the median lethal dose(LD50 ) to breast cancer cells. An innovative quantum similarity approach combining (self)-similarity indexes calculated with different charge-fitting schemes under the Topo-Geometrical Superposition Algorithm(TGSA) were used to obtain QSARs. The determination coefficient(R2 ) and leave-one-out cross-validation[Q2 (LOO)] quantified the quality of multiple linear regression and support vector machine models. This approach was efficient in predicting the activities, giving predictive and robust models for each endpoint [pLD50 : R2 =0.9666 and Q2 (LOO)=0.9312; pKi (CB1): R2 =1.0000 and Q2 (LOO)=0.9727, and pKi (CB2): R2 =0.9996 and Q2 (LOO)=0.9460], where p is the negative logarithm. The descriptors based on the electrostatic potential encrypted better electronic information involved in the interaction. Moreover, the similarity-based descriptors generated unbiased models independent of an alignment procedure. The obtained models showed better performance than those reported in the literature. An additional 3D-QSAR CoMFA analysis was applied to 15 cannabinoids, taking THC as a template in a ligand-based approach. From this analysis, the region surrounding the amino group of the SR141716 ligand is the more favorable for the antitumor activity.

Experimental Study of the Impact of Trace Amounts of Acetylene and Methylacetylene on the Synthesis, Mechanical and Thermal Properties of Polypropylene.

During the production of polymer-grade propylene, different processes are used to purify this compound and ensure that it is of the highest quality. However, some impurities such as acetylene and methyl acetylene are difficult to remove, and some of these impurities may be present in the propylene used to obtain polypropylene, which may have repercussions on the process. This study evaluates the impact of these acetylene and methyl acetylene impurities on the productivity of the polypropylene synthesis process and on the mechanical and thermal properties of the material obtained through the synthesis of eight samples with different concentrations of acetylene and eight samples with different concentrations of acetylene. We discovered that for the first concentrations of both acetylene (2 and 3 ppm) and methyl acetylene (0.03 and 0.1), the MFI, thermal recording, and mechanical properties of the resin were unaffected by the variation of the fluidity index, thermal degradation by TGA, and mechanical properties such as resistance to tension, bending, and impact. However, when the concentration exceeded 14 ppm for methyl acetylene and 12 ppm for acetylene, the resistance of this resin began to decrease linearly. Regarding production, this was affected by the first traces of acetylene and methyl acetylene progressively decreasing.

Biocatalysts Synthesized with Lipase from Pseudomonas cepacia on Glycol-Modified ZIF-8: Characterization and Utilization in the Synthesis of Green Biodiesel.

This research presents results on the production of biodiesel from the transesterification of acylglycerides present in palm oil, using the biocatalysts ZIF-8-PCL and Gly@ZIF-8-PCL synthesized by immobilization of Pseudomonas Cepacia Lipase as catalytic materials and using pure ZIF-8 and Gly@ZIF-8 (modified ZIF-8) as supports. The Gly@ZIF-8 carbonaceous material was prepared by wet impregnation of ZIF-8 with ethylene glycol as the carbon source, and then thermally modified. The calcination conditions were 900 °C for two hours with a heating rate of 7 °C/min in an inert atmosphere. A textural characterization was performed, and results showed superficial changes of materials at the microporous and mesoporous levels for the Gly@ZIF-8 material. Both the starting materials and biocatalysts were characterized by infrared spectroscopy (FTIR) and Raman spectroscopy. During the transesterification, using the two biocatalysts (ZIF-8-PCL and Gly@ZIF-8-PCL), two supernatant liquids were generated which were characterized by infrared spectroscopy (FTIR), gas chromatography coupled to mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR). The results show that the two routes of synthesis of supports from ZIF-8 will be configured as effective methods for the generation of effective biocatalysts for biodiesel production.

Acoplamiento molecular y modelado tridimensional por homología de flavonoides derivados de amentoflavona con las neuraminidasas H1N1 y H5N1 del virus de gripe aviar / Molecular docking and threedimensional homology modeling of flavonoids derived from amentoflavone with H1N1 and H5N1 neuraminidases of avian influenza virus / Modelagem de homologia tridimensional e de acoplamento molecular de flavonóides derivados de amentoflavona com as neuraminidases H1N1 e H5N1 do vírus da gripe aviária

Resumen El virus de la influenza A es el responsable de la gripe aviar, condición patológica que afecta principalmente aves, caballos y mamíferos marinos, sin embargo, el subtipo H5NI tiene la capacidad de infectar a los humanos de forma rápida, exponiéndolos a un posible evento pandémico. Por tanto, el objetivo de este estudio fue realizar el acoplamiento molecular y modelado tridimensional por homología de flavonoides derivados de amentoflavona con las neuraminidasas H1N1 y H5N1 del virus de gripe aviar. Inicialmente, se obtuvo por homología la estructura 3D de la neuraminidasa H1N1. Seguido, se realizó un acoplamiento molecular de H1N1 con seis ligandos (F36, Ginkgetin, 3S,3R, 5S,5R, 6S y 6R), y más adelante H5N1 y los ligandos F36, Ginkgetin, 5R y 6R. Finalmente, a los complejos obtenidos se les realizó un análisis de interacciones. Los resultados dejaron en evidencia una relación entre la actividad inhibitoria y las interacciones tipo puente de hidrógeno e hidrofóbicas formadas entre el sitio activo de las neuraminidasas y los ligandos. Además, se observó una mejora en la actividad inhibitoria de los ligandos para la estereoquímica tipo R y sustituyentes poco voluminosos. De ahí que se propongan la evaluación experimental de los ligandos 5R y 6R como potenciales inhibidores de H5N1.

Abstract The influenza A virus is responsible for bird flu; a pathological condition that mainly affects birds, horses, and marine mammals, however, the H5N' subtype can infect humans quickly; exposing them to a possible pandemic event. Therefore, the objective of this study was to carry out the molecular docking and three-dimensional homology modeling of flavonoids derived from amentoflavone with H'NI and H5NI neuraminidases of the avian influenza virus. Initially, the 3D structure of H1N1 neuraminidase was obtained by homology. Then, the molecular docking of H1N1 was carried out with six ligands (F36, Ginkgetin, 3S, 3R, 5S, 5R, 6S, and 6R), and subsequently H5N1 and F36, Ginkgetin, 5R, and 6R ligands. Finally, an interaction analysis of the proteinligand complex was performed. The results showed a relationship between the inhibitory activity of ligands and the hydrophobic and hydrogen bridge-type interactions. In addition, an improvement in the inhibitory activity of the ligands for R-type stereochemistry and small bulky substituents was observed. Thus, the experimental evaluation of the 5R and 6R ligands as potential H5N' inhibitors is proposed.

Resumo O vírus influenza A é responsável pela gripe aviária; condição patológica que afeta principalmente pássaros, cavalos e mamíferos marinhos, no entanto, o subtipo H5N' tem a capacidade de infectar humanos rapidamente; assim, expondo-os a um possível evento pandémico. Portanto, o objetivo deste estudo foi realizar o acoplamento e modelagem de homologia tridimensional de flavonóides derivados da amentoflavona com as neuraminidases H1N1 e H5N1 do vírus da influenza aviária. Inicialmente, a estrutura 3D da neuraminidase H1N1 foi obtida por homologia. Em seguida, o acoplamento molecular de H1N1 foi realizado com seis ligantes (F36, Ginkgetin, 3S, 3R, 5S, 5R, 6S e 6R) e, posteriormente, H5NI e os ligantes F36, Ginkgetin, 5R e 6R. Finalmente, uma análise de interação foi realizada nos complexos obtidos. Os resultados mostraram uma relação entre a atividade inibitória e as interações hidrofóbicas e do tipo ponte de hidrogénio formadas entre o sítio ativo das neuraminidases e os ligantes. Além disso, foi observada uma melhoria na atividade inibitória dos ligantes para a estereoquímica do tipo R e pequenos substituintes volumosos. Assim, é proposta a avaliação experimental dos ligantes 5R e 6R como potenciais inibidores do H5NI.

Artificial modification of the chemical composition of orange oil (Citrus sinensis L.) and its effect on larvicidal activity.

The use of synthetic pesticide carries along several disadvantages talking about the preservation of the natural homeostasis of the planet, causing the searching of biopesticide, which one presents advantages as well as biodegradability in minimum possible time, the low toxicity in comparison to synthetic pesticides and their variety of structure, which allows slowing down the appearance of resistance. The aim of this work was to evaluate the effect on the larvicidal action when artificially varying the chemical composition of orange oil (Citrus sinensis L.). As results, we found that the analysis of gas chromatography coupled to mass spectrometry showed the presence of terpenoid and sesquiterpenoid compounds in the different samples. The use of electric pulses on samples modified their chemical composition, so that the percentage of limonene went from 72% in the sample that was not subjected to electric treatment to lower percentages, even in sample three the percentage of limonene was <50%. Only three compounds (limonene, linalool and caryophyllene) were found to be common in all samples. Subsequently, the larvicidal action on Drosophila melanogaster larvae was evaluated. Six concentrations of each oil sample were tested (0, 100, 500, 1000, 5000 and 10000 ppm). We found that there was no linear relationship between concentration and lethality. Additionally, in the sample without electrical treatment most of the concentrations tested had lethality higher than 50%, while in sample 7 the results of the lethality were lower than 30%, so that biological tests showed that in samples where the concentration of limonene was lower, the lethality in the larvae decreased.

Diels-Alder Reactivity of a Chiral Anthracene Template with Symmetrical and Unsymmetrical Dienophiles: A DFT Study.

In this work, we used Density Functional Theory calculations to assess the factors that control the reactivity of a chiral anthracene template with three sets of dienophiles including maleic anhydrides, maleimides and acetoxy lactones in the context of Diels-Alder cycloadditions. The results obtained here (at the M06-2X/6-311++G(d,p) level of theory) suggest that the activation energies for maleic anhydrides and acetoxy lactones are dependent on the nature of the substituent in the dienophile. Among all studied substituents, only -CN reduces the energy barrier of the cycloaddition. For maleimides, the activation energies are independent of the heteroatom of the dienophile and the R group attached to it. The analysis of frontier molecular orbitals, charge transfer and the activation strain model (at the M06-2X/TZVP level based on M06-2X/6-311++G(d,p) geometries) suggest that the activation energies in maleic anhydrides are mainly controlled by the amount of charge transfer from the diene to the dienophile during cycloaddition. For maleimides, there is a dual control of interaction and strain energies on the activation energies, whereas for the acetoxy lactones the activation energies seem to be controlled by the degree of template distortion at the transition state. Finally, calculations show that considering a catalyst on the studied cycloadditions changes the reaction mechanism from concerted to stepwise and proceed with much lower activation energies.

Diels-Alder reaction mechanisms of substituted chiral anthracene: A theoretical study based on the reaction force and reaction electronic flux.

Quantum chemical calculations were used to study the mechanism of Diels-Alder reactions involving chiral anthracenes as dienes and a series of dienophiles. The reaction force analysis was employed to obtain a detailed scrutiny of the reaction mechanisms, it has been found that thermodynamics and kinetics of the reactions are quite consistent: the lower the activation energy, the lower the reaction energy, thus following the Bell-Evans-Polanyi principle. It has been found that activation energies are mostly due to structural rearrangements that in most cases represented more than 70% of the activation energy. Electronic activity mostly due to changes in σ and π bonding were revealed by the reaction electronic flux (REF), this property helps identify whether changes on σ or π bonding drive the reaction. Additionally, new global indexes describing the behavior of the electronic activity were introduced and then used to classify the reactions in terms of the spontaneity of their electronic activity. Local natural bond order electronic population analysis was used to check consistency with global REF through the characterization of specific changes in the electronic density that might be responsible for the activity already detected by the REF. Results show that reactions involving acetoxy lactones are driven by spontaneous electronic activity coming from bond forming/strengthening processes; in the case of maleic anhydrides and maleimides it appears that both spontaneous and non-spontaneous electronic activity are quite active in driving the reactions.

Homology Modeling of Leishmanolysin (gp63) from Leishmania panamensis and Molecular Docking of Flavonoids.

Leishmaniasis is a chronic disease caused by protozoa of the distinct Leishmania genus transmitted by sandflies of the genus Phlebotomus (old world) and Lutzomyia (new world). Among the molecular factors that contribute to the virulence and pathogenesis of Leishmania are metalloproteases, e.g., glycoprotein 63 (gp63), also known as leishmanolysin or major surface protease (MSP). This protease is a zinc-dependent metalloprotease that is found on the surface of the parasite, abundant in Leishmania promastigote and amastigote. This study describes the prediction of three-dimensional (3D) structures of leishmanolysin (UniProt ID A0A088RJX7) of Leishmania panamensis employing a homology modeling approach. The 3D structure prediction was performed using the SWISS-MODEL web server. The tools PROCHECK, Molprobyty, and Verify3D were used to check the quality of the model, indicating that they are reliable. Best docking configurations were identified applying AutoDock Vina in PyRx 0.8 to obtain a potential antileishmanial activity. Biflavonoids such as lanaroflavone, podocarpusflavone A, amentoflavone, and podocarpusflavone B showed good scores among these molecules. Lanaroflavone appears to be the most suitable compound from binding affinity calculations.

AMBER parameters and topology data of 2-pentylpyrrole adduct of arginine with 4-hydroxy-2-nonenal.

The data described here supports a part of the research article "Effect of 4­HNE Modification on ZU5-ANK Domain and the Formation of Their Complex with ß­Spectrin: A Molecular Dynamics Simulation Study" [1]. Dataset on Gaff force field parameters of AMBER is provided for the non-standard arginine resulting of reaction with 4-hydroxy-2-nonenal (4-HNE), the major secondary product of lipids peroxidation. Arg-HNE 2-pentilpyrrole adduct is part of the 4-hydroxyalkenals described in various physiopathological disorders related to increased oxidative stress. Data include a framework for derivation of missing bonds, angles and dihedral parameters for modified arginine, alongside optimized partial charges derived with Restrained Electrostatic Potential (RESP) method and the new force field parameters obtained by quantum mechanicals methods (QM) using Hartree-Fock (HF)/6 - 31G** level of theory. Benchmark as a graphics tutorial summary steps to obtained new parameters and the validation of non-standard amino acids is presented. The new residue constructed is put available to the scientific community to perform molecular dynamics simulations of modified 4-HNE proteins on arginine residue and complete the set of data parameters for nucleophilic residues with this reactive aldehyde ADDIN EN.CITE ADDIN EN.CITE.DATA [2]. Data that could be used for the researchers interested in the role of protein oxidation as mediator in cellular pathophysiological.

Distributed and multicore QuBiLS-MIDAS software v2.0: Computing chiral, fuzzy, weighted and truncated geometrical molecular descriptors based on tensor algebra.

Advances to the distributed, multi-core and fully cross-platform QuBiLS-MIDAS software v2.0 (http://tomocomd.com/qubils-midas) are reported in this article since the v1.0 release. The QuBiLS-MIDAS software is the only one that computes atom-pair and alignment-free geometrical MDs (3D-MDs) from several distance metrics other than the Euclidean distance, as well as alignment-free 3D-MDs that codify structural information regarding the relations among three and four atoms of a molecule. The most recent features added to the QuBiLS-MIDAS software v2.0 are related (a) to the calculation of atomic weightings from indices based on the vertex-degree invariant (e.g., Alikhanidi index); (b) to consider central chirality during the molecular encoding; (c) to use measures based on clustering methods and statistical functions to codify structural information among more than two atoms; (d) to the use of a novel method based on fuzzy membership functions to spherically truncate inter-atomic relations; and (e) to the use of weighted and fuzzy aggregation operators to compute global 3D-MDs according to the importance and/or interrelation of the atoms of a molecule during the molecular encoding. Moreover, a novel module to compute QuBiLS-MIDAS 3D-MDs from their headings was also developed. This module can be used either by the graphical user interface or by means of the software library. By using the library, both the predictive models built with the QuBiLS-MIDAS 3D-MDs and the QuBiLS-MIDAS 3D-MDs calculation can be embedded in other tools. A set of predefined QuBiLS-MIDAS 3D-MDs with high information content and low redundancy on a set comprised of 20,469 compounds is also provided to be employed in further cheminformatics tasks. This set of predefined 3D-MDs evidenced better performance than all the universe of Dragon (v5.5) and PaDEL 0D-to-3D MDs in variability studies, whereas a linear independence study proved that these QuBiLS-MIDAS 3D-MDs codify chemical information orthogonal to the Dragon 0D-to-3D MDs. This set of predefined 3D-MDs would be periodically updated as long as new results be achieved. In general, this report highlights our continued efforts to provide a better tool for a most suitable characterization of compounds, and in this way, to contribute to obtaining better outcomes in future applications.

Effect of 4-HNE Modification on ZU5-ANK Domain and the Formation of Their Complex with ß-Spectrin: A Molecular Dynamics Simulation Study.

4-HNE-modified ankyrins have been described in diseases such as diabetes, renal failure, G6PD deficient, sickle cell trait, and P. falciparum infected erythrocytes with different AB0 blood groups. However, effects at the atomic level of this carbonylation on structure and function of modified protein are not yet fully understood. We present a study based on molecular dynamics simulations of nine 4-HNE modified residues of the ZU5-ANK ankyrin domain with ß-spectrin and their binding energy profiles. Results show that 4-HNE induced local conformational changes over all protein systems evaluated, increased mobility in the modification sites, and localized structural changes between the positively charged patch of the ZU5-ANK domain. Carbonylation with 4-HNE on lysine residues decreased the affinity between ZU5-ANK and the 14-ß-spectrin repeat by reducing electrostatic and van der Waals interactions. The presented work provides further insight into understanding the loss of human erythrocyte deformation capacity under conditions of oxidative stress in different diseases.

Tensor Algebra-based Geometrical (3D) Biomacro-Molecular Descriptors for Protein Research: Theory, Applications and Comparison with other Methods.

In this report, a new type of tridimensional (3D) biomacro-molecular descriptors for proteins are proposed. These descriptors make use of multi-linear algebra concepts based on the application of 3-linear forms (i.e., Canonical Trilinear (Tr), Trilinear Cubic (TrC), Trilinear-Quadratic-Bilinear (TrQB) and so on) as a specific case of the N-linear algebraic forms. The definition of the kth 3-tuple similarity-dissimilarity spatial matrices (Tensor's Form) are used for the transformation and for the representation of the existing chemical information available in the relationships between three amino acids of a protein. Several metrics (Minkowski-type, wave-edge, etc) and multi-metrics (Triangle area, Bond-angle, etc) are proposed for the interaction information extraction, as well as probabilistic transformations (e.g., simple stochastic and mutual probability) to achieve matrix normalization. A generalized procedure considering amino acid level-based indices that can be fused together by using aggregator operators for descriptors calculations is proposed. The obtained results demonstrated that the new proposed 3D biomacro-molecular indices perform better than other approaches in the SCOP-based discrimination and the prediction of folding rate of proteins by using simple linear parametrical models. It can be concluded that the proposed method allows the definition of 3D biomacro-molecular descriptors that contain orthogonal information capable of providing better models for applications in protein science.

Evaluación teórica de las propiedades electrónicas y estructurales que afectan a la conductividad eléctrica en copolímeros de furano-tiofeno / Theoretical evaluation of the electronic and structural properties that affect the electrical conductivity in furan-thiophene copolymers / Avaliação teórica das propriedades eletrônicas e estruturais que afetam à condutividade eléctrica em copolímeros de furano-tiofeno

Resumen Desde el punto de vista científico y tecnológico ha habido un gran interés en el uso de monosustituyentes de furano y tiofeno como polímeros conductores, debido a sus múltiples aplicaciones como OLED, amplificadores ópticos, nanotecnología, entre otros. Por ello, el propósito de este trabajo fue estudiar los aspectos teóricos que afectan las propiedades electroconductoras de este tipo de moléculas. Se determinaron teóricamente los aspectos estructurales y electrónicos que influyeron en la conductividad de copolímeros de furano-tiofeno monosustituidos, al utilizar grupos carboxilos, metilos, hidroxilos, ciano y fluoruros como sustituyentes en el carbono C3 y C10 de cada heterociclo. La diferencia de energía entre el LUMO y el HOMO (band gap, Eg) y el potencial de ionización (PI) fue calculada a partir de las geometrías optimizadas en DFT para el estado neutro, anión y catión. Los PI y la Eg de los copolímeros fueron obtenidos mediante la extrapolación de los valores del oligómero a (1/N) y de una cadena de longitud infinita (1/N=0), obteniéndose una correlación lineal (R=0,99), la cual se mantiene a lo largo de todos los modelos de ajuste de cada copolímero analizado en el estudio.

Abstract There has been great scientific and technological interest in the use of mono-substituents of furan and thiophene as conducting polymers due to their multiple applications such as OLED, optical amplifiers and nanotechnology, among others. For this, the purpose of this work was to study the theoretical aspects that affect the electroconductive properties of this type of molecules. The structural and electronic properties that influence the conductivity of mono substituted-furan-thiophene copolymers were determined theoretically. The effect of using carboxyl, methyl, hydroxyl, cyano, and fluoride groups as substituents on the carbon C3 and C10 of each heterocycle was observed. The energy difference between the LUMO and the HOMO (band gap, Eg) and the ionization potential (IP) were calculated from the geometries optimized in DFT for the neutral, anion and cation state. The PI and Eg of the copolymers were obtained by extrapolating the values of the oligomer a (1/N) and a chain of infinite length (1/N=0) for which a linear correlation was obtained (R=0.99). This correlation is maintained throughout all the adjustment models of each copolymer analyzed in the study.

Resumo Existe muito interesse os termos científicos e tecnológicos em utilizar substituintes mono-substituídos furano e tiofeno como polímeros condutores devido às suas múltiplas aplicações, tais como OLED, amplificadores ópticos e nanotecnologia, entre outros. O objetivo deste trabalho foi estudar os aspectos teóricos que afetam as propriedades eletrocondutoras deste tipo de moléculas. Neste contribuição os aspectos estruturais e electrónicas que influenciam a condutividade de copolímeros furano-tiofeno substituos mono teoricamente determinada observando o efeito do uso de grupos carboxilo, metilo, hidroxilo, ciano e fluoretos como substituintes em C3 e C10 de carbono de cada heterociclo. A diferença de energia entre o LUMO e o HOMO (intervalo de banda, Eg) e o potencial de ionização (IP) foram calculadas a partir das geometrias optimizadas de DFT para o estado neutro, anião e catião. O PI e o Eg dos copolímeros foram obtidos por extrapolação dos valores do oligómero (1/N) e extrapolando para uma cadeia de comprimento infinito (1/ N=0) para os quais uma correlação linear foi obtida (R=0,99), que é mantido ao longo de todos os modelos de ajuste de cada copolímero analisados no estudo.

Higher-Order and Mixed Discrete Derivatives such as a Novel Graph- Theoretical Invariant for Generating New Molecular Descriptors.

BACKGROUND: Recently, some authors have defined new molecular descriptors (MDs) based on the use of the Graph Discrete Derivative, known as Graph Derivative Indices (GDI). This new approach about discrete derivatives over various elements from a graph takes as outset the formation of subgraphs. Previously, these definitions were extended into the chemical context (N-tuples) and interpreted in structural/physicalchemical terms as well as applied into the description of several endpoints, with good results. OBJECTIVE: A generalization of GDIs using the definitions of Higher Order and Mixed Derivative for molecular graphs is proposed as a generalization of the previous works, allowing the generation of a new family of MDs. METHODS: An extension of the previously defined GDIs is presented, and for this purpose, the concept of Higher Order Derivatives and Mixed Derivatives is introduced. These novel approaches to obtaining MDs based on the concepts of discrete derivatives (finite difference) of the molecular graphs use the elements of the hypermatrices conceived from 12 different ways (12 events) of fragmenting the molecular structures. The result of applying the higher order and mixed GDIs over any molecular structure allows finding Local Vertex Invariants (LOVIs) for atom-pairs, for atoms-pairs-pairs and so on. All new families of GDIs are implemented in a computational software denominated DIVATI (acronym for Discrete DeriVAtive Type Indices), a module of KeysFinder Framework in TOMOCOMD-CARDD system. RESULTS: QSAR modeling of the biological activity (Log 1/K) of 31 steroids reveals that the GDIs obtained using the higher order and mixed GDIs approaches yield slightly higher performance compared to previously reported approaches based on the duplex, triplex and quadruplex matrix. In fact, the statistical parameters for models obtained with the higher-order and mixed GDI method are superior to those reported in the literature by using other 0-3D QSAR methods. CONCLUSION: It can be suggested that the higher-order and mixed GDIs, appear as a promissory tool in QSAR/QSPRs, similarity/dissimilarity analysis and virtual screening studies.

Study of interaction energies between residues of the active site of Hsp90 and geldanamycin analogues using quantum mechanics/molecular mechanics methods.

Background: Heat shock protein (Hsp90KDa) is a molecular chaperone involved in the process of cellular oncogenesis, hence its importance as a therapeutic target. Geldanamycin is an inhibitor of Hsp90 chaperone activity, which binds to the ATP binding site in the N-terminal domain of Hsp90. However, geldanamycin has shown hepatotoxic damage in clinical trials; for this reason, its use is not recommended. Taking advantage that geldanamycin binds successfully to Hsp90, many efforts have focused on the search for similar analogues, which have the same or better biological response and reduce the side effects of its predecessor; 17-AAG and 17-DMAG are examples of these analogues. Methods: In order to know the chemical factors influencing the growth or decay of the biological activity of geldanamycin analogues, different computational techniques such as docking, 3DQSAR and quantum similarity were used.  Moreover, the study quantified the interaction energy between amino acids residues of active side and geldanamycin analogues, through hybrid methodology (Autodock-PM6) and DFT indexes. Results: The evaluation of interaction energies showed that the interaction with Lys58 residue is essential for the union of the analogues to the active site of Hsp90, and improves its biological activity. This union is formed through a substituent on C-11 of the geldanamycin macrocycle. A small and attractor group was found as the main steric and electrostatic characteristic that substituents on C11 need in order to interact with Lys 58; behavior was observed with hydroxy and methoxy series of geldanamycin analogues, under study. Conclusion: This study contributes with new hybrid methodology (Autodock-PM6) for the generation of 3DQSAR models, which to consider the interactions between compounds and amino acids residues of Hsp90´s active site in the alignment generation. Additionally, quantum similarity and reactivity indices calculations using DFT were performed to know the non-covalent stabilization in the active site of these compounds.

4-HNE carbonylation induces local conformational changes on bovine serum albumin and thioredoxin. A molecular dynamics study.

4-hydroxy-2-nonenal (4-HNE) is the main end product of peroxidation in lipids, capable of introduce carbonyl groups to nucleophilic amino acids via Michael additions and alter protein function. It has been reported that 4-HNE protein carbonylation is associated with intracellular protein aggregation, the pathogenesis of neurodegenerative and metabolic diseases and yet it is unclear how the carbonylation affects the protein structure and dynamics at the atomic level. Here, we analysis the structural effects of 4-HNE modification through formation of Michael adducts of Cys-4HNE, His-4HNE and Lys-4HNE on Serum Albumin (BSA) and Thioredoxin (TRX). Since both proteins have experimental evidence to possess 4-HNE-modifications on cysteine, histidine and lysine residues, extended molecular dynamics simulations were performed with AMBER to study the carbonylation effects in the structure of these proteins. BSA is the main protein of plasma while TRX is an important antioxidant enzyme. Results showed local changes and alteration in the conformational stability, folding and flexibility after including the 4-HNE modification. DSSP analysis showed important structural modifications as a consequence of the inclusion of the modified residues. Analysis of the computed trajectories suggests that 4-HNE decreases stability, increases local flexibility and produced modest unfolding on both tested proteins. Finally, all the systems evaluated shown an increase in the lipophilic potential and a modest decrease in the electrostatic potential in BSA but an increase in TRX.

The role of LasR active site amino acids in the interaction with the Acyl Homoserine Lactones (AHLs) analogues: A computational study.

The present work combines molecular docking calculations, 3D-QSAR, molecular dynamics simulations and free binding energy calculations (MM/PBSA and MM/GBSA) in a set of 28 structural analogues of acyl homoserine lactones with Quorum Sensing antagonist activity. The aim of this work is to understand how ligand binds and is affected by the molecular microenvironment in the active site of the LasR receptor for pseudomonas aeruginosa. We also study the stability of the interaction to find key structural characteristics that explain the antagonist activities of this set of ligands. This information is relevant for the rational modification or design of molecules and their identification as powerful LasR modulators. The analysis of molecular docking simulations shows that the 28 analogues have a similar binding mode compared to the native ligand. The carbonyl groups belonging to the lactone ring and the amide group of the acyl chain are oriented towards the amino acids forming hydrogen bond like interactions. The difference in antagonist activity is due to location and orientation of the LasR side chains within the hydrophobic pocket in its binding site. Additionally, we carried out molecular dynamics simulations to understand the conformational changes in the ligand-receptor interaction and the stability of each complex. Results show a direct relationship among the interaction energies of the ligands and the activities as an antagonist of the LasR receptor.

Choquet integral-based fuzzy molecular characterizations: when global definitions are computed from the dependency among atom/bond contributions (LOVIs/LOEIs).

BACKGROUND: Several topological (2D) and geometric (3D) molecular descriptors (MDs) are calculated from local vertex/edge invariants (LOVIs/LOEIs) by performing an aggregation process. To this end, norm-, mean- and statistic-based (non-fuzzy) operators are used, under the assumption that LOVIs/LOEIs are independent (orthogonal) values of one another. These operators are based on additive and/or linear measures and, consequently, they cannot be used to encode information from interrelated criteria. Thus, as LOVIs/LOEIs are not orthogonal values, then non-additive (fuzzy) measures can be used to encode the interrelation among them. RESULTS: General approaches to compute fuzzy 2D/3D-MDs from the contribution of each atom (LOVIs) or covalent bond (LOEIs) within a molecule are proposed, by using the Choquet integral as fuzzy aggregation operator. The Choquet integral-based operator is rather different from the other operators often used for the 2D/3D-MDs calculation. It performs a reordering step to fuse the LOVIs/LOEIs according to their magnitudes and, in addition, it considers the interrelation among them through a fuzzy measure. With this operator, fuzzy definitions can be derived from traditional or recent MDs; for instance, fuzzy Randic-like connectivity indices, fuzzy Balaban-like indices, fuzzy Kier-Hall connectivity indices, among others. To demonstrate the feasibility of using this operator, the QuBiLS-MIDAS 3D-MDs were used as study case and, as a result, a module was built into the corresponding software to compute them ( http://tomocomd.com/qubils-midas ). Thus, it is the only software reported in the literature that can be employed to determine Choquet integral-based fuzzy MDs. Moreover, regression models were created on eight chemical datasets. In this way, a comparison between the results achieved by the models based on the non-fuzzy QuBiLS-MIDAS 3D-MDs with regard to the ones achieved by the models based on the fuzzy QuBiLS-MIDAS 3D-MDs was made. As a result, the models built with the fuzzy QuBiLS-MIDAS 3D-MDs achieved the best performance, which was statistically corroborated through the Wilcoxon signed-rank test. CONCLUSIONS: All in all, it can be concluded that the Choquet integral constitutes a prominent alternative to compute fuzzy 2D/3D-MDs from LOVIs/LOEIs. In this way, better characterizations of the compounds can be obtained, which will be ultimately useful in enhancing the modelling ability of existing traditional 2D/3D-MDs.

Reduction of Hexavalent Chromium and Detection of Chromate Reductase (ChrR) in Stenotrophomonas maltophilia.

An Gram negative strain of S. maltophilia, indigenous to environments contaminated by Cr(VI) and identified by biochemical methods and 16S rRNA gene analysis, reduced chromate by 100%, 98-99% and 92% at concentrations in the 10-70, 80-300, and 500 mg/L range, respectively at pH 7 and temperature 37 °C. Increasing concentrations of Cr(VI) in the medium lowered the growth rate but could not be directly correlated with the amount of Cr(VI) reduced. The strain also exhibited multiple resistance to antibiotics and tolerance and resistance to various heavy metals (Ni, Zn and Cu), with the exception of Hg. Hexavalent chromium reduction was mainly associated with the soluble fraction of the cell evaluated with crude cell-free extracts. A protein of molecular weight around 25 kDa was detected on SDS-PAGE gel depending on the concentration of hexavalent chromium in the medium (0, 100 and 500 mg/L). In silico analysis in this contribution, revealed the presence of the chromate reductase gene ChrR in S. maltophilia, evidenced through a fragment of around 468 bp obtained experimentally. High Cr(VI) concentration resistance and high Cr(VI) reducing ability of the strain make it a suitable candidate for bioremediation.

Synthesis, Anti-Proliferative Activity Evaluation and 3D-QSAR Study of Naphthoquinone Derivatives as Potential Anti-Colorectal Cancer Agents.

Colorectal cancer (CRC) is a disease with high incidence and mortality, constituting the fourth most common cause of death from cancer worldwide. Naphthoquinones are attractive compounds due to their biological and structural properties. In this work, 36 naphthoquinone derivatives were synthesized and their activity evaluated against HT-29 cells. Overall, high to moderate anti-proliferative activity was observed in most members of the series, with 15 compounds classified as active (1.73 < IC50 < 18.11 µM). The naphtho[2,3-b]thiophene-4,9-dione analogs showed potent cytotoxicity, 8-hydroxy-2-(thiophen-2-ylcarbonyl)naphtho[2,3-b]thiophene-4,9-dione being the compound with the highest potency and selectivity. Our results suggest that the toxicity is improved in molecules with tricyclic naphtho[2,3-b]furan-4,9-dione and naphtho[2,3-b]thiophene-4,9-dione systems 2-substituted with an electron-withdrawing group. A 3D-QSAR study of comparative molecular field analysis (CoMFA) was carried out, resulting in the generation of a reliable model (r² = 0.99 and q² = 0.625). This model allowed proposing five new compounds with two-fold higher theoretical anti-proliferative activity, which would be worthwhile to synthesize and evaluate. Further investigations will be needed to determine the mechanism involved in the effect of most active compounds which are potential candidates for new anticancer agents.