Spin Energy Contributions of the Kinetic Energy Density in the Stabilization of the Metal-Ligand Interactions.

The kinetic energy (KE) density plays an essential role in the stabilization mechanism of covalent, polar covalent, and ionic bondings; however, its role in metal-ligand bindings remains unclear. In a recent work, the energetic contributions of the spin densities α and ß were studied to explain the geometrical characteristics of a series of metal-ligand complexes. Notably, the KE density was found to modulate/stabilize the spin components of the intra-atomic nucleus-electron interactions within the metal in the complex. Here, we investigate the topographic properties of the spin components of the KE density for a family of high-spin hexa-aquo complexes ([M(H2O)6]2+) to shed light on the stabilization of the metal-ligand interaction. We compute the Lagrangian, G(r), and Hamiltonian, K(r), KE densities and analyze the evolution of its spin components in the formation of two metal-ligand coordination complexes. We study Kα/ß(r) along the metal-oxygen (M-O) internuclear axis as a function of the metal. Our results indicate that K(r) is a more distance-sensitive quantity compared to G(r) as it displays topographic features at larger M-O distances. Furthermore, K(r) allows one to identify the predominant interaction mechanism in the complexes.

Stereoelectronic interactions are too weak to explain the molecular conformation in solid state of cis-2-tert-butyl-5-(tert-butylsulfonyl)-1,3-dioxane.

cis-2-tert-Butyl-5-(tert-butylsulfonyl)-1,3-dioxane (cis-1) exhibits a high degree of eclipsing in the H-C5-S-C segment in the solid state, the origin of which remains unexplained. The eclipsed conformation that corresponds to an energetic minimum in the solid state practically corresponds to a rotational transition state in solution, which allows an approach to understand transitions states. The difference in the enthalpy of sublimation ΔsubH between cis-1 and the more stable trans-1 is 8.40 kcal mol-1, lets to consider that the intermolecular interactions in the crystalline structure must be responsible for the conformational effect observed in the solid state. The study of the experimental electron density of cis-1 in solid state allowed to establish that CH⋯OS intermolecular interaction is the main contribution to the observed eclipsing. The charge density analysis was also performed using the quantum theory of atoms in molecules to evaluate the nature and relevance of the intermolecular interactions in the crystal structure.

Hydrolysis of ester phosphates mediated by a copper complex.

Phosphate ester hydrolysis is an important reaction that plays a major role in both enzymatic and non-enzymatic processes, including DNA and pesticide breaking. Although it is a widely studied reaction, the precise mechanistic details, especially for copper complexes, remain under discussion. To contribute to the debate, we present the catalyzed hydrolysis of phosphomono-, di- and tri-esters mediated by the [Cu(II)(1,10-phenanthroline)] complex. The reaction coordinates for several substrates were explored through the metadynamics formalism. Thus, we found that for mono- and di-substituted ester phosphates a concerted mechanism is observed, where a coordinated hydroxyl group attacks the phosphorus atom at the same side as the leaving group, along with a proton transfer. In contrast, tri-substituted phosphate remains coordinated with the metal, and the nucleophile acts independently following an addition-elimination process. That is, the metallic complex achieves a specific nucleophile-phosphate interaction that produces a concerted transition state in the phosphoester hydrolysis process.

How do density functionals affect the Hirshfeld atom refinement?

In this work, the effect of mixing different amounts of Hartree-Fock (HF) exchange with hybrid density functionals applied to the Hirshfeld atom refinement (HAR) of urea and oxalic acid dihydrate is explored. Together, the influence of using different basis sets, methods (including MP2 and HF) and cluster sizes (to model bulk effects) is studied. The results show that changing the amount of HF exchange, no matter the level of theory, has an impact almost exclusively on the H atom refinement parameters. Contrary to pure quantum mechanical calculations where good geometries are obtained with intermediate HF exchange mixtures, in the HAR the best match with neutron diffraction reference values is not necessarily found for these admixtures. While the non-hydrogen covalent bond lengths are insensitive to the combination of method or basis set employed, the X-H bond lengths always increase proportionally to the HF exchange for the analysed systems. This outcome is opposite to what is normally observed from geometry optimisations, i.e., shorter bonds are obtained with greater HF exchange. Additionally, the thermal ellipsoids tend to shrink with larger HF exchange, especially for the H atoms involved in strong hydrogen bonding. Thus, it may be the case that the development of density functionals or basis sets suitable for quantum crystallography should take a different path than those fitted for quantum chemistry calculations.

DNA recognition site of anticancer tinidazole copper(II) complexes.

This paper describes the recognition process of tetrahedral [CuII(tnz)2X2] (X = Cl, Br) complexes by a DNA chain, analyzing the specific interaction between the DNA bases and backbone with the metal and the tinidazole (tnz) ligand. We identified the coordination of the copper metal center with one or two phosphates as the first recognition site for the tinidazole copper(II) complexes, while the ligands present partial intercalation into the minor groove. Also, we discuss a novel trigonal copper(I) tnz bromide complex, obtained by reducing the previously reported [Cu(tnz)2Br2]. This complex sheds light on the mechanism of action of tnz metal complexes as one of the most stable DNA-complex adducts depicts a trigonal geometry around the copper ion.

How solvent determines the molecular reactive conformation and the selectivity: Solvation spheres and energy.

In solution, the solvent determines the molecular conformation and the chemical reaction viability and selectivity. When solvent-solute and solvent-solvent interactions present similar strengths, explicit salvation is the best way to describe a system. The problem to solve is how big the explicit shell should be. In this paper, we want to answer one of the fundamental questions in the implementation of explicit solvation, exactly how many solvent molecules should be added and where they should be placed. Here we determine the first solvent sphere around a molecule and describe how it controls the conformation and selectivity of a selected reaction. NMR experiments were carried out to identify the number of solvent molecules around the solute that constitutes the first solvent sphere, and the interaction between this solvent sphere and the solute was detected using DFT and QTAIM calculations. A new approach to the solvation energy is presented. Finally, we established the role of solvent molecules in the conformation of the solute and in the transition states that produce the two possible products of the reaction.

Benzene and Borazine, so Different, yet so Similar: Insight from Experimental Charge Density Analysis.

Although benzene and borazine are isoelectronic and isostructural, they have very different electronic structures, mainly due to the polar nature of the B-N bond. Herein, we present an experimental study of the charge density distribution obtained from the multipole model formalism and Hirshfeld atom refinement (HAR) based on high-resolution X-ray diffraction data of borazine B3N3H6 (1) and B,B',B″-trichloroborazine (2) crystals. These data are compared to those obtained from HAR for benzene (4) and 1,3,5-trichlorobenzene (5) and further compared with values obtained from density functional theory calculations in the gas phase, where N,N',N″-trichloroborazine (3) was also included. The results confirm that, unlike benzene, borazines are only weakly aromatic with an island-like electronic delocalization within the B3N3 ring involving only the nitrogen atoms. Furthermore, delocalization indices and interacting quantum atom energy for bonded and non-bonded atoms were found to be highly suitable indicators capable of describing the origin of the discrepancies observed when the degree of aromaticity in 2 and 3 is evaluated using common aromaticity indices. Additionally, analysis of intermolecular interactions in the crystals brings further evidence of a weakly aromatic character of the borazines as it reveals surprising similarities between the crystal packing of borazine and benzene and also between B,B',B″-trichloroborazine and 1,3,5-trichlorobenzene.

Excited state dynamics and photochemistry of nitroaromatic compounds.

Nitrated aromatic molecules have unique photoinduced channels. Due to the presence of oxygen-centered non-bonding orbitals, they can undergo sub-picosecond intersystem crossing showing one of the strongest couplings between the singlet and triplet manifolds among organic molecules. Several nitroaromatic compounds also have a distinctive nitric oxide photodissociation channel which occurs through a complex sequence of atom rearrangements and state changes. These remarkable processes have stimulated the attention of several research groups over the last few years who have applied modern femtosecond spectroscopies and new computational methods to these topics. Nitroaromatic molecules also have demonstrated their value as case-studies, where they can serve to understand the influence of torsional motions between the nitro substituent and the aromatic system in the conversions between states. In this contribution we highlight several of the recent results in this area. Due to the importance of the atmospheric photochemistry of nitrated compounds and their accumulating applications as nitric oxide release agents, continued research about the effects of the different state orderings, substitution patterns, and solvent effects is central to the development of future applications and for a better understanding of their environmental pathways. From this analysis, several pending issues are highlighted, which include the nature of the dominant singlet state involved in intersystem crossing, the role of the formation of charge-transfer states, the yield of the internal conversion channel to the electronic ground state, and a more generalized understanding of the sequence of steps which lead to nitric oxide dissociation.

Intermediate Detection in the Casiopeina-Cysteine Interaction Ending in the Disulfide Bond Formation and Copper Reduction.

A strategy to improve the cancer therapies involves agents that cause the depletion of the endogenous antioxidant glutathione (GSH), increasing its efflux out of cells and inducing apoptosis in tumoral cells due to the presence of reactive oxygen species. It has been shown that Casiopeina copper complexes caused a dramatic intracellular GSH drop, forming disulfide bonds and reducing CuII to CuI. Herein, through the determination of the [CuII]-SH bond before reduction, we present evidence of the adduct between cysteine and one Casiopeina as an intermediate in the cystine formation and as a model to understand the anticancer activity of copper complexes. Evidence of such an intermediate has never been presented before.

Ancillary Ligand in Ternary CuII Complexes Guides Binding Selectivity toward Minor-Groove DNA.

Copper-containing compounds known as Casiopeínas are biologically active molecules which show promising antineoplastic effects against several cancer types. Two possible hypotheses regarding the mode of action of the Casiopeínas have emerged from the experimental evidence: the generation of reactive oxygen species or the ability of the compounds to bind and interact with nucleic acids. Using robust molecular dynamics simulations, we investigate the interaction of four different Casiopeínas with the DNA duplex d(GCACGAACGAACGAACGC). The studied copper complexes contain either 4-7- or 5-6-substituted dimethyl phenanthroline as the primary ligand and either glycinate or acetylacetonate as the secondary ligand. For statistical significance and to reduce bias in the simulations, four molecules of each copper compound were manually placed at a distance of 10 Å away from the DNA and 20 independent molecular dynamics simulations were performed, each reaching at least 30 µs. This time scale allows us to reproduce expected DNA terminal base-pair fraying and also to observe intercalation/base-pair eversion events generated by the compounds interacting with DNA. The results reveal that the secondary ligand is the guide toward the mode of binding between the copper complex and DNA in which glycinate prefers minor-groove binding and acetylacetonate produces base-pair eversion and intercalation. The CuII complexes containing glycinate interact within the DNA minor groove which are stabilized principally by the hydrogen bonds formed between the amino group of the aminoacidate moiety, whereas the compounds with the acetylacetonate do not present a stable network of hydrogen bonds and the ligand interactions enhance DNA breathing dynamics that result in base-pair eversion.

Do weak interactions affect the biological behavior of DNA? A DFT study of CpG island-like chains.

The origin, stability, and contribution to the formation of noncovalent interactions, such as hydrogen bonds and π - π stacking, have been already widely discussed. However, there are few discussions about the relevance of these weak interactions in DNA performance. In this work, we seek to shed light on the effect of hydrogen bonds and π - π stacking interactions on the biological behavior of DNA through the description of these intermolecular forces in CpG island-like (GC-rich) chains. Furthermore, we made some comparisons with TATA box-like (TA-rich) chains in order to describe hydrogen bond and π - π stacking interactions as a function of the DNA sequence. For hydrogen bonds, we found that there is not a significant effect related to the number of base pairs. Whereas for π - π stacking interactions, the energy tended to decrease as the number of base pairs increased. We observed anticooperative effects for both hydrogen bonds and π - π stacking interactions. These results are in contrast with those of TATA box-like chains since cooperative and additive effects were found for both hydrogen bonds and π - π stacking, respectively. Based on the chemical hardness and density of states, we can conclude that proteins may interact easier with GC-rich chains. We conclude that regardless of the chain length, a protein could interact more easily with these genomics regions because the π - π stacking energies did not increase as a function of the number of base pairs, making, for the first time, a first approximation of the influence of noncovalent interaction on DNA behavior. We did all this work by means of DFT framework included in the DMol3 code (M06-L/DNP). Graphical Abstract Cartoon representation of how nocovalent interactions affect the interaction of DNA with a protein, i.e., how hydrogen bond and π - π stacking interactions influence the biological behavior of DNA.

From the Linnett-Gillespie model to the polarization of the spin valence shells of metals in complexes.

In this paper, we present a novel approach to track the origin of the metal complex structure from the topology of the α and ß spin densities as an extension of the Linnett-Gillespie model. Usually, the theories that explain the metal-ligand interactions consider the disposition and the relative energies of the empty or occupied set of d orbitals, ignoring the spin contribution explicitly. Our quantum topological approach considers the spatial distribution of the α and ß spin valence shells, and the energy interaction between them. We used the properties of the atomic graph, a topological object that summarises the charge concentrations and depletions on the valence shell of an atom in a molecule, and the interacting quantum atoms (IQA) energy partition scheme. Unlike the Linnett-Gillespie model, which is based on electron-electron repulsion, our approach states that the ligands provoke a redistribution of the electron density to maximize the nuclear-electron interactions in each spin valence shell to bypass the concentration of electron-electron interactions, resulting in a polarization pattern which determines the position of the ligands.

Predicting reactive sites with quantum chemical topology: carbonyl additions in multicomponent reactions.

Quantum Chemical Topology (QCT) is a well established structural theoretical approach, but the development of its reactivity component is still a challenge. The hypothesis of this work is that the reactivity of an atom within a molecule is a function of its electronic population, its delocalization in the rest of the molecule, and the way it polarizes within an atomic domain. In this paper, we present a topological reactivity predictor for cabonyl additions, κ. It is a measure of the polarization of the electron density with the carbonyl functional group. κ is a model obtained from a QSAR procedure, using quantum-topological atomic descriptors and reported hydration equilibrium constants of carbonyl compounds. To validate the predictive capability of κ, we applied it to organic reactions, including a multicomponent reaction. κ was the only property that predicts the reactivity in each reaction step. The shape of κ can be interpreted as the change between two electrophilic states of a functional group, reactive and non-reactive.

Laplacian of the Hamiltonian Kinetic Energy Density as an Indicator of Binding and Weak Interactions.

The kinetic energy is the center of a controversy between two opposite points of view about its role in the formation of a chemical bond. One school states that a lowering of the kinetic energy associated with electron delocalization is the key stabilization mechanism of covalent bonding. In contrast, the opposite school holds that a chemical bond is formed by a decrease in the potential energy due to a concentration of electron density within the binding region. In this work, a topographic analysis of the Hamiltonian Kinetic Energy Density (KED) and its laplacian is presented to gain more insight into the role of the kinetic energy within chemical interactions. This study is focused on atoms, diatomic and organic molecules, along with their dimers. In addition, it is shown that the laplacian of the Hamiltonian KED exhibits a shell structure in atoms and that their outermost shell merge when a molecule is formed. A covalent bond is characterized by a concentration of kinetic energy, potential energy and electron densities along the internuclear axis, whereas a charge-shift bond is characterized by a fusion of external concentration shells and a depletion in the bonding region. In the case of weak intermolecular interactions, the external shell of the molecules merge into each other resulting in an intermolecular surface comparable to that obtained by the Non-covalent interaction (NCI) analysis.

Enhancing Acute Oral Toxicity Predictions by using Consensus Modeling and Algebraic Form-Based 0D-to-2D Molecular Encodes.

Quantitative structure-activity relationships (QSAR) are introduced to predict acute oral toxicity (AOT), by using the QuBiLS-MAS (acronym for quadratic, bilinear and N-Linear maps based on graph-theoretic electronic-density matrices and atomic weightings) framework for the molecular encoding. Three training sets were employed to build the models: EPA training set (5931 compounds), EPA-full training set (7413 compounds), and Zhu training set (10 152 compounds). Additionally, the EPA test set (1482 compounds) was used for the validation of the QSAR models built on the EPA training set, while the ProTox (425 compounds) and T3DB (284 compounds) external sets were employed for the assessment of all the models. The k-nearest neighbor, multilayer perceptron, random forest, and support vector machine procedures were employed to build several base (individual) models. The base models with REPA-training ≥ 0.75 ( R = correlation coefficient) and MAEEPA-training ≤ 0.5 (MAE = mean absolute error) were retained to build consensus models. As a result, two consensus models based on the minimum operator and denoted as M19 and M22, as well as a consensus model based on the weighted average operator and denoted as M24, were selected as the best ones for each training set considered. According to the applicability domain (AD) analysis performed, model M19 (built on the EPA training set) has MAEtest-AD = 0.4044, MAEProTox-AD = 0.4067 and MAET3DB-AD = 0.2586 on the EPA test set, ProTox external set, and T3DB external set, respectively; whereas model M22 (built on the EPA-full set) and model M24 (built on the Zhu set) present MAEProTox-AD = 0.3992 and MAET3DB-AD = 0.2286, and MAEProTox-AD = 0.3773 and MAET3DB-AD = 0.2471 on the two external sets accounted for, respectively. These outcomes were compared and statistically validated with respect to 14 QSAR methods (e.g., admetSAR, ProTox-II) from the literature. As a result, model M22 presents the best overall performance. In addition, a retrospective study on 261 withdrawn drugs due to their toxic/side effects was performed, to assess the usefulness of prospectively using the QSAR models proposed in the labeling of chemicals. A comparison with regard to the methods from the literature was also made. As a result, model M22 has the best ability of labeling a compound as toxic according to the globally harmonized system of classification and labeling of chemicals. Therefore, it can be concluded that the models proposed, especially model M22, constitute prominent tools for studying AOT, at providing the best results among all the methods examined. A freely available software was also developed to be used in virtual screening tasks ( http://tomocomd.com/apps/ptoxra ).

Reactivity patterns for the activation of CO2 and CS2 with alumoxane and aluminum hydrides.

Carbon dioxide is readily fixed when reacting with either alumoxane dihydride [{MeLAl(H)}2(µ-O)] (1) or aluminum dihydride [MeLAlH2] (2) (MeL = HC[(CMe)N(2,4,6-Me3C6H2)]2-) to produce bimetallic aluminum formates [(MeLAl)2(µ-OCHO)2(µ-O)] (3) and [(MeLAl)2(µ-OCHO)2(µ-H)2] (5), respectively. Furthermore, [(MeLAl)2(µ-OCHO)2(µ-OH)2] (4) is easily obtained upon the reaction of 3 or 5 with H2O. The stability of the unusual dialuminum diformate dihydride core observed in 5 stems from the proximity of the Al centers allowing the formation of two Al-HAl bridges and precluding further hydride transfer to the HCO2 moieties. Contrary to this behavior, 1 and 2 react with CS2 giving cyclic alumoxane and aluminum sulfides [(MeLAl)2(µ-S)(µ-O)] (6) and [{MeLAl(µ-S)}2] (7), respectively. The molecular structures of 3-7 were characterized by IR, Raman, solution or solid-state (MAS) NMR spectroscopy and mass spectrometry and for 4-7 were characterized by X-ray diffraction studies. NMR kinetic studies and DFT calculations suggest that the mechanisms for the formation of 6 and 7 involve the transfer of a hydride group forming transient aluminum thioformate intermediates which proceed to form Al-S-Al moieties through the cleavage of C-S bonds and insertion of a sulfur atom, followed by the elimination of thioformaldehyde.

Distribution of toxicity values across different species and modes of action of pesticides from PESTIMEP and PPDB databases.

The continuous use of compounds contained in commodities such as processed food, medicines, and pesticides, demands safety measures, in particular, for those in direct contact with humans and the environment. Safety measures have evolved and regulations are now in place around the globe. In the case of pesticides, attempts have been made to use toxicological data to inform of potentially harmful compounds either across species, on different routes of exposure, or entirely new chemicals. The generation of models, based on statistical and molecular modeling studies, allows for such predictions. However, the use of these models is framed by the available data, the experimental errors, the complexity of the measurement, and the available computational algorithms, among other factors. In this work, we present the methodologies used for extrapolation across different species and routes of administration and show the appropriateness of developing predictive models of pesticides based on their type and mode of action. The analyses include comparisons based on structural characteristics and physicochemical properties. Whenever possible, the scope and limitations of the methodologies are discussed. We expect that this work will serve as a useful introductory guide of the tools employed in the toxicity assessment of agrochemical compounds.

Self-Assembly of Aluminum- and Gallium-Based meso-Metallaporphyrins.

The molecular meso-metallaporphyrin has been obtained from the reaction of AlMe3 with the bulky 4,5-(Ph2(HO)C)2-1,2,3-triazole (1). The presence of Al-Me groups coordinated to the triazole rings creates three different stereoisomers that were identified by single-crystal X-ray diffraction. Further studies revealed that, for steric reasons, only one of the two main stereoisomers is active in the polymerization of ε-caprolactone. When GaMe3 is used instead of AlMe3, a trimetallic species is formed instead of the meso-metallaporphyrin pointing to a metal-directed self-assembly. On the other hand, the reaction of the monolithium salt [{Li(THF)2}{κ2- N, N'-4,5-(Ph2(HO)C)-1,2,3-triazole}]2 (2; THF = tetrahydrofuran) with MCl3 (M = Al, Ga) yields meso-metallaporphyrin species with a lithium atom in the center of the metallacycle. While the gallium derivative is rather stable in solution, the aluminum analogue decomposes rapidly. In the solid state, continuous cationic columns running throughout the whole crystal are formed from alternating Li⊂[M]4 (M = Al, Ga) meso-metallaporphyrin and [Li(THF)4]+ cations. Density functional theory calculations determined that the weak Cl···H, H···H, N···H, and Cl···O interactions with a total interaction energy of -38.6 kcal·mol-1 are responsible for this unusual packing.

Origin of the Photoinduced Geometrical Change of Copper(I) Complexes from the Quantum Chemical Topology View.

Copper(I) complexes (CICs) are of great interest due to their applications as redox mediators and molecular switches. CICs present drastic geometrical change in their excited states, which interferes with their luminescence properties. The photophysical process has been extensively studied by several time-resolved methods to gain an understanding of the dynamics and mechanism of the torsion, which has been explained in terms of a Jahn-Teller effect. Here, we propose an alternative explanation for the photoinduced structural change of CICs, based on electron density redistribution. After photoexcitation of a CIC (S0 →S1 ), a metal-to-ligand charge transfer stabilizes the ligand and destabilizes the metal. A subsequent electron transfer, through an intersystem crossing process, followed by an internal conversion (S1 →T2 →T1 ), intensifies the energetic differences between the metal and ligand within the complex. The energy profile of each state is the result of the balance between metal and ligand energy changes. The loss of electrons originates an increase in the attractive potential energy within the copper basin, which is not compensated by the associated reduction of the repulsive atomic potential. To counterbalance the atomic destabilization, the valence shell of the copper center is polarized (defined by ∇2 ρ(r) and ∇2 Vne (r)) during the deactivation path. This polarization increases the magnitude of the intra-atomic nuclear-electron interactions within the copper atom and provokes the flattening of the structure to obtain the geometry with the maximum interaction between the charge depletions of the metal and the charge concentrations of the ligand.

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.