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.

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.

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.

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.

Physico-Chemical and Structural Interpretation of Discrete Derivative Indices on N-Tuples Atoms.

This report examines the interpretation of the Graph Derivative Indices (GDIs) from three different perspectives (i.e., in structural, steric and electronic terms). It is found that the individual vertex frequencies may be expressed in terms of the geometrical and electronic reactivity of the atoms and bonds, respectively. On the other hand, it is demonstrated that the GDIs are sensitive to progressive structural modifications in terms of: size, ramifications, electronic richness, conjugation effects and molecular symmetry. Moreover, it is observed that the GDIs quantify the interaction capacity among molecules and codify information on the activation entropy. A structure property relationship study reveals that there exists a direct correspondence between the individual frequencies of atoms and Hückel's Free Valence, as well as between the atomic GDIs and the chemical shift in NMR, which collectively validates the theory that these indices codify steric and electronic information of the atoms in a molecule. Taking in consideration the regularity and coherence found in experiments performed with the GDIs, it is possible to say that GDIs possess plausible interpretation in structural and physicochemical terms.

Mechanism for the uncatalyzed cyclic acetone-peroxide formation reaction: an experimental and computational study.

In this study, a mechanism for the uncatalyzed reaction between acetone and hydrogen peroxide is postulated. The reaction leads to the formation of the important homemade explosives collectively known as cyclic acetone peroxides (CAP). The proposed mechanistic scheme is based on Raman, GC-MS, and nuclear magnetic resonance measurements, and it is supported by ab initio density functional theory (DFT) calculations. The results demonstrate that the proposed mechanism for the uncatalyzed formation reaction of CAP occurs in three steps: monomer formation, polymerization of the 2-hydroperoxipropan-2-ol monomer, and cyclization. The temporal decay of the intensities of important assigned-bands is in excellent agreement with the proposed mechanism. Previous reports also confirm that the polymerization step is favored in comparison to other possible pathways.

Design of Angiotensin-converting Enzyme 2 (ACE2) Inhibitors by Virtual Lead Optimization and Screening.

A group of presumed drug-like molecules that possess high in silico affinity for angiotensin-converting enzyme 2 were computationally designed. This enzyme is a promising new target in both cardiorenal disease and some coronavirus infections. A set of substrate analogous molecules were optimized by means of the LeapFrog module of the SYBYL package. Later, Molinspiration and Molsoft were used for screening out the compounds with low oral bioavailability. Similarly, OSIRIS was used for screening out the compounds having serious side effects. At the end of several stages of screening, seven candidates to anti-viral drugs fulfiling all the evaluated criteria were obtained. They are amenable for future studies in vitro and in vivo. These designed ligands were finally evaluated by Quantitative Structure Activity Relationship studies. 21 molecules were used to carry out the qsar models. Fom these four molecules were taken as external sets yielding models with q 2 = 0.652 and r 2 = 0.962 values.

Quantum mechanics study of the hydroxyethylamines-BACE-1 active site interaction energies.

The identification of BACE-1, a key enzyme in the production of Amyloid-ß (Aß) peptides, generated by the proteolytic processing of amyloid precursor protein, was a major advance in the field of Alzheimer's disease as this pathology is characterized by the presence of extracellular senile plaques, mainly comprised of Aß peptides. Hydroxyethylamines have demonstrated a remarkable potential, like candidate drugs, for this disease using BACE-1 as target. Density Functional Theory calculations were employed to estimate interaction energies for the complexes formed between the hydroxyethylamine derivated inhibitors and 24 residues in the BACE-1 active site. The collected data offered not only a general but a particular quantitative description that gives a deep insight of the interactions in the active site, showing at the same time how ligand structural variations affect them. Polar interactions are the major energetic contributors for complex stabilization and those ones with charged aspartate residues are highlighted, as they contribute over 90% of the total attractive interaction energy. Ligand-ARG296 residue interaction reports the most repulsive value and decreasing of the magnitude of this repulsion can be a key feature for the design of novel and more potent BACE-1 inhibitors. Also it was explained why sultam derivated BACE-1 inhibitors are better ones than lactam based. Hydrophobic interactions concentrated at S1 zone and other relevant repulsions and attractions were also evaluated. The comparison of two different theory levels (X3LYP and M062X) allowed to confirm the relevance of the detected interactions as each theory level has its own strength to depict the forces involved, as is the case of M062X which is better describing the hydrophobic interactions. Those facts were also evaluated and confirmed by comparing the quantitative trend, of selected ligand-residue interactions, with MP2 theory level as reference standard method for electrostatic plus dispersion energies.

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.

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.

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.

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.

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.

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.

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.