DFT Descriptors Research Articles

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

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

Effect of the central atom and donor on linear and nonlinear optical properties of tricyanopyrrolidone derivatives: DFT and TD-DFT approach

We have designed 50 molecules having “donor-π-acceptor system.” Different donors connected to tricyanopyrrolidone acceptor with 10 different heteroatom units are selected to study their “ground state” structural and nonlinear optical (NLO) properties. Frontier molecular orbital (FMO), molecular electrostatic potential (MEP) plots, and bond length alteration (BLA) showed intramolecular charge transfer (ICT). Results suggest that HOMO-LUMO energies of selected dyes depend on donor strength and heteroatoms. Triphenylamine substituted donors showed red-shifted vertical excitations, higher dipole moments, and higher hyperpolarizabilities. Using DFT, NLO parameters such as (β0) and (γ) are calculated with three different functionals, including global hybrid (GH), B3LYP and range separated CAM-B3LYP, and ωB97XD functionals. Molecular reactivity descriptors, chemical potential (μ), chemical hardness (η), electrophilicity index (ω), and hyperhardness (Γ) are produced. DFT descriptors are correlated with calculated NLO parameters.

Symmetry and reactivity of π-systems in electric and magnetic fields: a perspective from conceptual DFT.

The extension of conceptual density-functional theory (conceptual DFT) to include external electromagnetic fields in chemical systems is utilised to investigate the effects of strong magnetic fields on the electronic charge distribution and its consequences on the reactivity of π-systems. Formaldehyde, H2CO, is considered as a prototypical example and current-density-functional theory (current-DFT) calculations are used to evaluate the electric dipole moment together with two principal local conceptual DFT descriptors, the electron density and the Fukui functions, which provide insight into how H2CO behaves chemically in a magnetic field. In particular, the symmetry properties of these quantities are analysed on the basis of group, representation, and corepresentation theories using a recently developed automatic program for symbolic symmetry analysis, QSYM2. This allows us to leverage the simple symmetry constraints on the macroscopic electric dipole moment components to make profound predictions on the more nuanced symmetry transformation properties of the microscopic frontier molecular orbitals (MOs), electron densities, and Fukui functions. This is especially useful for complex-valued MOs in magnetic fields whose detailed symmetry analyses lead us to define the new concepts of modular and phasal symmetry breaking. Through these concepts, the deep connection between the vanishing constraints on the electric dipole moment components and the symmetry of electron densities and Fukui functions can be formalised, and the inability of the magnetic field in all three principal orientations considered to induce asymmetry with respect to the molecular plane of H2CO can be understood from a molecular perspective. Furthermore, the detailed forms of the Fukui functions reveal a remarkable reversal in the direction of the dipole moment along the CO bond in the presence of a parallel or perpendicular magnetic field, the origin of which can be attributed to the mixing between the frontier MOs due to their subduced symmetries in magnetic fields. The findings in this work are also discussed in the wider context of a long-standing debate on the possibility to create enantioselectivity by external fields.

Quantum Chemical GA-MLR, Cluster Model, and Conceptual DFT Descriptors Studies on the Binding Interaction of Estrogen Receptor Alpha with Endocrine Disrupting Chemicals

In the present study, the predication of the binding affinity (log RBA) of estrogen receptor alpha with three categories of environmental endocrine disrupting chemicals (EDCs), namely, PCB, phenol, and DDT, is performed by the quantum chemical genetic algorithm multiple linear regression (GA-MLR) method. The result of the optimal model indicates that log RBA increases with increasing the electrophilicity and hydrophobicity of EDCs. However, by using the quantum chemical cluster model approach, the modeling results reveal that electrostatic interaction and hydrogen bonding play a significant role. The chemical reactivity descriptors calculated based on the conceptual density functional theory also indicate that the binding mechanism of charge-controlled interaction is superior to that of frontier-controlled interaction.

Polyradical character assessment using multireference calculations and comparison with density-functional derived fractional occupation number weighted density analysis.

The biradicaloid character of different types of polycyclic aromatic hydrocarbons (PAHs) based on small band gaps is an important descriptor to assess their opto-electronic properties. In this work, the unpaired electron densities and numbers of unpaired electrons (NU values) calculated at the high-level multireference averaged quadratic coupled-cluster (MR-AQCC) method are used to develop a test set to assess the capabilities of different biradical descriptors based on density functional theory. A benchmark collection of 29 different compounds has been selected. The DFT descriptors contain primarily the fractional occupation number weighted electron density (FOD) based on simplified thermally-assisted-occupation density functional theory (TAO-DFT) calculations, but the singlet-triplet energy difference and other descriptors denoted as y0 and nLUNO have been considered as well. After adjustment of the literature-recommended finite temperatures, a very good, detailed agreement between unpaired density and FOD analysis is observed which is also manifested in excellent statistical correlations. The other two descriptors also show good correlations even though the absolute scaling is not satisfactory. A new linear fit of FOD data to the MR-AQCC reference values leads to an improved regression relation for determining the recommended finite temperature value in dependence of the Hartree-Fock exchange. This provides the basis for fast and reliable assessment of the biradical character of many classes of PAHs without the need for performing computationally extended MR calculations.

Effective removal of cationic dye on activated carbon made from cactus fruit peels: a combined experimental and theoretical study.

This article investigates experimentally and theoretically the adsorption of Basic Red 46 cationic dye (BR46) using activated carbon generated from cactus fruit peels (ACCFP). The prepared adsorbent was characterized by different analytical tools showing a good surface for the uptake of pollutants. A maximum batch adsorption capacity of 806.38 mg g-1 was achieved at optimal conditions. The Freundlich model best represented the equilibrium data, although the pseudo-second-order kinetic model best described the adsorption kinetics. The thermodynamic studies demonstrated that the adsorption process was spontaneous (ΔG° < 0) and endothermic (ΔH° = 32.512 kJ mol-1). DFT descriptors were combined with COSMO-RS and AIM theory to provide a complete picture of the adsorbate/adsorbent system and its molecular interactions. Last, the ACCFP was regenerable up to four times, emphasizing the idea of using it as an adsorbent to treat textile wastewaters.

A Quantum Chemical Deep-Dive into the π-π Interactions of 3-Methylindole and Its Halogenated Derivatives-Towards an Improved Ligand Design and Tryptophan Stacking.

Non-covalent π-π stacking interactions often play a key role in the stability of the secondary and tertiary structures of peptides and proteins, respectively, and can be a means of ensuring the binding of ligands within protein and enzyme binding sites. It is generally accepted that minor structural changes to the aromatic ring, such as substitution, can have a large influence on these interactions. Nevertheless, a thorough understanding of underpinning phenomena guiding these key interactions is still limited. This is especially true for larger aromatic structures. To expand upon this knowledge, elaborate ab initio calculations were performed to investigate the effect of halogenation on the stability of 3-methylindole stacking. 3-Methylindole served as a representation of the tryptophan side chain, and is a frequently used motif in drug design and development. Moreover, an expression is derived that is able to accurately predict the interaction stability of stacked halogenated 3-methylindole dimers as well as halogenated toluene dimers, based on monomer level calculated DFT descriptors. We aim for this expression to provide the field with a straightforward and reliable method to assess the effect of halogenation on the π-π stacking interactions between aromatic scaffolds.

Halogen-Based 17β-HSD1 Inhibitors: Insights from DFT, Docking, and Molecular Dynamics Simulation Studies.

The high expression of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) mRNA has been found in breast cancer tissues and endometriosis. The current research focuses on preparing a range of organic molecules as 17β-HSD1 inhibitors. Among them, the derivatives of hydroxyphenyl naphthol steroidomimetics are reported as one of the potential groups of inhibitors for treating estrogen-dependent disorders. Looking at the recent trends in drug design, many halogen-based drugs have been approved by the FDA in the last few years. Here, we propose sixteen potential hydroxyphenyl naphthol steroidomimetics-based inhibitors through halogen substitution. Our Frontier Molecular Orbitals (FMO) analysis reveals that the halogen atom significantly lowers the Lowest Unoccupied Molecular Orbital (LUMO) level, and iodine shows an excellent capability to reduce the LUMO in particular. Tri-halogen substitution shows more chemical reactivity via a reduced HOMO–LUMO gap. Furthermore, the computed DFT descriptors highlight the structure–property relationship towards their binding ability to the 17β-HSD1 protein. We analyze the nature of different noncovalent interactions between these molecules and the 17β-HSD1 using molecular docking analysis. The halogen-derived molecules showed binding energy ranging from −10.26 to −11.94 kcal/mol. Furthermore, the molecular dynamics (MD) simulations show that the newly proposed compounds provide good stability with 17β-HSD1. The information obtained from this investigation will advance our knowledge of the 17β-HSD1 inhibitors and offer clues to developing new 17β-HSD1 inhibitors for future applications.

Machine learning predictive classification models for the carcinogenic activity of activated metabolites derived from aromatic amines and nitroaromatics

A 3D-QSAR study based on DFT descriptors and machine learning calculations is presented in this work. Our goal has been to build predictive models for classifying the carcinogenic activity of a set of aromatic amines (AA) and nitroaromatic (NA) compounds. As the main result, we stress that calculations must consider both the activated metabolites (derived from AA and NA species) and the water solvent to obtain reliable predictive classification models. We have obtained eight decision tree models that presented an accuracy of over 90% by using either Gázquez-Vela chemical potential (μ+) or the chemical hardness (η) of the activated metabolites in aqueous solvent.

Imidazolium based superalkalis as building block for Lewis base

Inquest for efficient Lewis base an in-silico investigation on NH3 and its structurally similar molecules has been carried out. It has been observed that the ionization energy of the groups attached to the N-centre plays a vital role in determining their stability and reactivity. Among different groups, superalkali ligands make a better Lewis base. Several conceptual DFT descriptors like electrophilicity, nucleophilicity, dual descriptors have been used to analyse the stability and reactivity of the proposed Lewis base. The calculated charge transfer descriptor describes the efficiency of the designed Lewis base to form an adduct with Lewis acid. nc-2e (n = 1,2) AdNDP calculation lends additional support to the bonding of the studied molecules.

Biotransformation of BPA via epoxidation catalyzed by Cytochrome P450

Metabolites formed during the biotransformation mediated by CYP450 may turn toxic. Investigations upon the mechanism involved in the formation of such toxic byproducts are important in analyzing their potential threat and also in elucidating the pathway for their removal. Bisphenols belong to the class of omnipresent phytochemicals. Eventually this leads to their higher exposure to humans. Therefore, preventions for the toxicity in BPA (2, 2-bis (4-hydroxyphenyl propane) has been of utmost priority. However, the mechanisms involved in their biotransformation are still a domain of topical interest.Since, epoxides are not commonly found in nature and are usually produced due to interaction of alkenes or olefins from CYP450. In the present article, efforts have been made to investigate the toxicity and mechanism involved in the formation of epoxide intermediate of bisphenol catalyzed through CYP450. Theoretical methods are utilized to investigate the mechanism, involved energetics, electronic reorganizations, structural information, barrier heights and DFT descriptors of the reactant & product, during the course of the reaction to elucidate the formation of epoxide product. The reaction mechanism was found to be stepwise and prefers low spin surface in the epoxidation process. Also, the epoxide metabolite formed after epoxidation was found to be more toxic than the parent compound.

2D‐QSAR and molecular docking studies of carbamate derivatives to discover novel potent anti‐butyrylcholinesterase agents for Alzheimer's disease treatment

AbstractCurrently, anti‐butyrylcholinesterase (anti‐BuChE)is among the greatest therapeutic agents for the treatment of Alzheimer's disease. In this research, a series of 36 carbamate derivatives were subjected to a quantitative structure–activity relationships study using DFT and Lipinski's descriptors. Multiple linear regression (MLR) was used to explore the relationships between the structural features of these compounds and BuChE inhibitory activity. In order to generate results applicable in the experimental plan, the Organization of Economic Cooperation and Development guidelines were adopted. The quality of MLR model was evaluated by several statistical parameters including internal and external validation parameters (R2, R2adj, F, VIF, R2test, Q2CV, R2Rand, Q2CV [Rand], and cRp2). The built model displayed a high predictive power (R2test = 0.817). What is more, the internal validation parameters (Q2CV = 0.774; average R2Rand = 0.118; average Q2CV [Rand] = −0.438; cRp2 = 0.820) highlight the robustness of our built model. Besides, the obtained result revealed that anti‐BuChE activity is mainly attributed to the following molecular descriptors: octanol–water partition (log P), highest occupied molecular orbital energy (EHOMO), total energy (ET), and dipole moment (μ). Based on these findings, a series of newer synthesizable compounds with enhanced anti‐BuChE activities were designed and their ADMET and drug‐likeness properties were further predicted to filter out compounds likely to fail during drug development stages. Finally, molecular docking and molecular dynamics were performed to identify the binding types between the best designed compounds and BuChE enzyme.

Predicting Solvent-Dependent Nucleophilicity Parameter with a Causal Structure Property Relationship

Solvent-dependent reactivity is a key aspect of synthetic science, which controls reaction selectivity. The contemporary focus on new, sustainable solvents highlights a need for reactivity predictions in different solvents. Herein, we report the excellent machine learning prediction of the nucleophilicity parameter N in the four most-common solvents for nucleophiles in the Mayr's reactivity parameter database (R2 = 0.93 and 81.6% of predictions within ±2.0 of the experimental values with Extra Trees algorithm). A Causal Structure Property Relationship (CSPR) approach was utilized, with focus on the physicochemical relationships between the descriptors and the predicted parameters, and on rational improvements of the prediction models. The nucleophiles were represented with a series of electronic and steric descriptors and the solvents were represented with principal component analysis (PCA) descriptors based on the ACS Solvent Tool. The models indicated that steric factors do not contribute significantly, because of bias in the experimental database. The most important descriptors are solvent-dependent HOMO energy and Hirshfeld charge of the nucleophilic atom. Replacing DFT descriptors with Parameterization Method 6 (PM6) descriptors for the nucleophiles led to an 8.7-fold decrease in computational time, and an ∼10% decrease in the percentage of predictions within ±2.0 and ±1.0 of the experimental values.

Positional isomers of heterocyclic azo dyes: Investigation of NLO properties by Z-scan and correlative DFT studies

We report four azo dyes and their positional isomers having a benzothiazole-pyridone core. Selected heterocyclic emissive azo dyes in this work are analysed for their non-linear optical (NLO) properties. Non-linear absorptive coefficient (β), non-linear refractive index (ƞ2), third-order NLO susceptibility (χ3), and optical limiting (OL) in different solvents are analysed and promising results are obtained using Z-scan technique. Laser damage threshold (LDT) and thermogravimetric analysis (TGA) supports that these dyes can be a good constructive unit in laser assisted devices and several high-temperature NLO processes respectively. Molecular electrostatic potential (MEP), Frontier molecular orbitals (FMOs) are also presented using B3LYP/6–311+ G (d,p) level of theory. Global hybrid functional (GH) and Range separated hybrid functional (RSH) i.e. B3LYP, BHandHLYP and CAM-B3LYP, ωB97, ωB97X, ωB97X-D respectively used for the calculation of NLO parameters. Limits of hyperpolarizabilities and intrinsic hyperpolarizabilities are calculated and all the hyperpolarizabilities of the molecules are within estimated limits. HOMO-LUMO gap have an inverse correlation with the experimental non-linear optical susceptibility (χ3). Inverse or direct correlation with hyperpolarizability with different DFT descriptors such as electrophilicity index (ω), hyperhardness is also presented.

Synthesis, Experimental and DFT Studies of Some Benzotriazole Derivatives as Brass C68700 Corrosion Inhibitors in NaCl 3 %

AbstractCorrosion inhibition potential of three synthesized benzotriazole (BTA) derivatives namely, 1‐(prop‐2‐yn‐1‐yl)‐1H‐benzotriazole (Inh 1), 2‐[2‐(1H‐benzotriazol‐1‐yl)ethyl]‐1H‐isoindole‐1,3(2H)‐dione (Inh 2) and 1‐(4‐nitrobenzyl)‐1H‐1,2,3‐benzotriazole (Inh 3), on brass C68700 in NaCl 3 % was evaluated using potentiodynamic method. The results show that the examined molecules are good inhibitors for brass and behave as mixed type inhibitors. Inhibition efficiency (IE %) increases with the inhibitors concentration to reach 80.89 %, 83.70 % and 92.13 % at 15 ppm for Inh 1, Inh 2 and Inh 3 respectively. Additionally, the calculated DFT descriptors are in good agreement with the experimental inhibition efficiencies.

Synthesis, characterization, theoretical calculations (DFT and MC), and experimental of different substituted pyridine derivatives as corrosion mitigation for X-65 steel corrosion in 1M HCl

Newly synthesized ρ-substituted pyridine derivatives (PYR-Cl, PYR-H, and PYR-OCH3) were characterized by FT-IR, MS, and 1HNMR. Quantum calculations indicate the insight compounds have active adsorption centers that suppress X-65 steel dissolution via DFT descriptors and MC simulation calculations. Electrochemical (potentiodynamic polarization and impedance) techniques were employed to investigate the inhibition performance of the studied substituted pyridine derivatives. The tendency of the studied pyridine derivatives to shield X-65 steel surface away from the HCl aggressiveness action depends on electron-donating and withdrawing effect of ρ-substitution groups (-Cl, -OCH3), according to Hammett constant (σ), and their addition concentrations. Tafel data indicated that the inhibition efficiency touches the peak (95.75%) at 1 × 10−3 M PYR-OCH3 at 25°C. The ρ-substituted pyridine derivatives adsorbed chemically and physically over X-65 steel surface (ΔGads ≈-38 kJmol−1) and followed the Langmuir adsorption isotherm model. Surface morphology (SEM and EDX) displayed the smooth X-65 steel surface due to the adsorbed-protective layer's formation. Both theoretical and experimental studies confirm the inhibition efficacy order of the tested pyridine derivatives, PYR-Cl < PYR-H < PYR-OCH3.

Comparison of donors julolidine and triphenylamine in TCF-based NLOphoric dyes – a DFT approach

Julolidine or TPA donor and tricyanofuran acceptor systems are selected to assess the ‘ground state molecular aspects’ and NLO properties of dyes. Six different functionals with five solvents are used to compute vertical excitations and hyperpolarizabilities. The trends in vertical excitations seen in B3LYP functional are comparable with experimental absorption maxima. Intramolecular charge transfer studies correlated with hyperpolarizabilities. The amplitude of sine-shaped potential decreases with an increase in the conjugation chain and solvent polarity. Perturbation potentials have correlation with BLA, quinoid character, hyperpolarizabilities. Increase or decrease in the HOMO–LUMO also depends on the solvent environment. Hyperpolarizabilities, β 0 and γ depend on the solvent polarity and the trends are similar in six different functionals. Standard deviation (SD) is used to benchmark the functional performance. Different DFT descriptors including the relatively new ‘hyperhardness’ are correlated with calculated NLO parameters. Correlations are quantitatively analysed using regression coefficients. DFT studies show that selected dyes can stand as good NLO material.

Charge Transfer Parameters, Correlative Perturbation Potential with Non‐Linear Optical Properties of Bi‐Heterocyclic Dyes Having TCF Acceptor‐ DFT Approach

AbstractWe have designed ten molecules having “donor‐π‐acceptor system”. Coumarin and carbazole connected to tricyanofuran acceptor unit are selected to study their “ground state” structural and NLO properties. Six functionals with five solvents are used to obtain vertical excitation and hyperpolarizabilities. “Amplitude of sine‐shaped potential” decreases with increase in conjugation chain and solvent polarity. Frontier molecular orbital (FMO), molecular electrostatic potential (MEPS), bond length alteration (BLA), quinoid character (δr) showed intramolecular charge transfer (ICT). HOMO‐LUMO depends on donor strength and solvent environment. N‐Alkyl substituted donors showed red shifted vertical excitations, higher dipole moments and higher hyperpolarizabilities. Perturbation potential have correlation with BLA, quinoid character, hyperpolarizabilities and hyperhardness. Using DFT, NLO parameters such as‐(β0) and (γ) are calculated with six different functionals‐ including global hybrid (GH) and range separated hybrid (RSH) (B3LYP, BHandHLYP, CAM‐B3LYP, ωB97, ωB97X, and ωB97X‐D). Higher (β0) 213×10−30(esu) and (γ) 791×10−30(esu) obtained using B3LYP functional for NCou 1. Standard deviation and mean absolute error calculated to check usefulness of functional. DFT descriptors, chemical potential (μ), chemical hardness (η), electrophilicity index (ω) and hyperhardness are produced. DFT descriptors are correlated with calculated NLO parameters.

Solvent Effects on Thiol–Ene Kinetics and Reactivity of Carbon and Sulfur Radicals

The thiol-ene reaction is one of the fundamental reactions in biochemistry and synthetic organic chemistry. In this study, the effect of polar media on the reaction kinetics is taken into account by using the transition state theory; the reactivities of the carbon and sulfur radicals have also been rationalized by using conceptual DFT. The results have shown that the solvents have more impact on hydrogen atom transfer reactions and the chain transfer rate constant, kCT, can be increased by using nonpolar solvents, while propagation reactions are less sensitive to media. Similarly, the kP/kCT ratio can be manipulated by changing the environment in order to obtain tailor-made polymers. Regarding the DFT descriptors, the local and global electrophilicity indices are well correlated with the propagation rate constant kP, whereas the global electrophilicity index is associated with the chain transfer rate constant kCT. Overall, electrophilicity indices can be used with confidence to predict the kinetics of thiol-ene reactions.

Substituent Effect on the Himbert Intramolecular Arene/Allene Diels-Alder Reaction: NBO Analysis and State Specific Dual Descriptors.

Conceptual density functional theory has been applied to study the Himbert intramolecular arene/allene Diels-Alder reaction. The effect of substitutions at different positions on the kinetics of these reactions has been analyzed. Therefore, from the calculation of the activation energies of more than 27 reactions involving concerted mechanisms, the selectivity of these reactions can be predicted and rationalized with the aid of conceptual DFT descriptors. An application of the two concepts, natural population analysis (NBO) and the state-specific dual descriptor (SSDD) for evaluating substituent effects, allows the investigation of the different interactions that promote a reaction compared to another. The SSDDs computed for the transition state structures provide important information about charge transfer interactions during the chemical reaction. In our case, the SSDD results show that the substituents promoting Himbert reaction have the lowest excitation energies, a fact which facilitates the allene/arene interaction. The NBO results show that according to the nature of the substituent, the Himbert reaction stands as a normal-electron demand or reverse. Thus, the interactions favoring each reaction are mentioned. The geometric deformation observed in the case of OCH3 is at the origin to the emergence of other low interactions between diene and dienophile as well as a strong electronic delocalization stabilizing the arene moiety. The calculated synchronicity indexes show that the Himbert intramolecular Diels-Alder reactions are very synchronous.