Elucidation of Molecular Mechanism of a Selective PPARα Modulator, Pemafibrate, through Combinational Approaches of X-ray Crystallography, Thermodynamic Analysis, and First-Principle Calculations.

The selective PPARα modulator (SPPARMα) is expected to medicate dyslipidemia with minimizing adverse effects. Recently, pemafibrate was screened from the ligand library as an SPPARMα bearing strong potency. Several clinical pieces of evidence have proved the usefulness of pemafibrate as a medication; however, how pemafibrate works as a SPPARMα at the molecular level is not fully known. In this study, we investigate the molecular mechanism behind its novel SPPARMα character through a combination of approaches of X-ray crystallography, isothermal titration calorimetry (ITC), and fragment molecular orbital (FMO) analysis. ITC measurements have indicated that pemafibrate binds more strongly to PPARα than to PPARγ. The crystal structure of PPARα-ligand binding domain (LBD)/pemafibrate/steroid receptor coactivator-1 peptide (SRC1) determined at 3.2 Å resolution indicates that pemafibrate binds to the ligand binding pocket (LBP) of PPARα in a Y-shaped form. The structure also reveals that the conformation of the phenoxyalkyl group in pemafibrate is flexible in the absence of SRC1 coactivator peptide bound to PPARα; this gives a freedom for the phenoxyalkyl group to adopt structural changes induced by the binding of coactivators. FMO calculations have indicated that the accumulation of hydrophobic interactions provided by the residues at the LBP improve the interaction between pemafibrate and PPARα compared with the interaction between fenofibrate and PPARα.

Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl-Chain Length and Hepatic Insulin Sensitivity in Mice.

BACKGROUND AND AIMS: Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. APPROACH AND RESULTS: To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver-specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet-induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatin-like phospholipase domain-containing protein 3 (Pnpla3) expression was down-regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to inhibitor 2 of PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6-ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum and a Pnpla3-CerS4 complex on lipid droplets. Consistent with this, liver-specific Elovl6 deletion in ob/ob mice reduced both hepatic ceramide(d18:1/18:0) and PP2A activity and ameliorated insulin resistance. CONCLUSIONS: Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl-chain composition of ceramide and that C18:0-ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3-mediated NAFLD.

Total Synthesis of Termicalcicolanone A via Organocatalysis and Regioselective Claisen Rearrangement.

A total synthesis of an anticancer xanthone natural product termicalcicolanone A utilizing multiple nucleophilic aromatic substitutions and pericyclic reactions has been developed. The pyrano[3,2- b]xanthen-6-one scaffold was constructed via NHC-catalyzed aroylation to produce the benzophenone intermediate, Claisen cyclization to form the pyran ring, and intramolecular 1,4-addition to construct the xanthone framework. The prenyl group was introduced in the final stages of the synthesis through regioselective Claisen rearrangement. The synthesis has been achieved in 19 steps.

Dual conformation of the ligand induces the partial agonistic activity of retinoid X receptor α (RXRα).

1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic acid (CBt-PMN), a partial agonist of retinoid X receptor (RXR), has attracted attention due to its potential to treat type 2 diabetes and central nervous system diseases with reduced adverse effects of existing full agonists. Herein, we report the crystal structure of CBt-PMN-bound ligand-binding domain of human RXRα (hRXRα) and its biochemical characterization. Interestingly, the structure is a tetramer in nature, in which CBt-PMNs are clearly found binding in two different conformations. The dynamics of the hRXRα/CBt-PMN complex examined using molecular dynamics simulations suggest that the flexibility of the AF-2 interface depends on the conformation of the ligand. These facts reveal that the dual conformation of CBt-PMN in the complex is probably the reason behind its partial agonistic activity.

Molecular association model of PPARα and its new specific and efficient ligand, pemafibrate: Structural basis for SPPARMα.

Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor involved in the regulation of lipid homeostasis and improves hypertriglyceridemia. Pemafibrate is a novel selective PPARα modulator (SPPARMα) that activates PPARα transcriptional activity. Here, we computationally constructed the structure of the human PPARα in a complex with pemafibrate, along with that of hPPARα complexed with the classical fenofibrate, and studied their interactions quantitatively by using the first-principles calculations-based fragment molecular orbital (FMO) method. Comprehensive structural and protein-ligand binding elucidation along with the in vitro luciferase analysis let us to identify pemafibrate as a novel SPPARMα. Unlike known fibrate ligands, which bind only with the arm I of the Y-shaped ligand binding pocket, the Y-shaped pemafibrate binds to the entire cavity region. This lock and key nature causes enhanced induced fit in pemafibrate-ligated PPARα. Importantly, this selective modulator allosterically changes PPARα conformation to form a brand-new interface, which in turn binds to PPARα co-activator, PGC-1α, resulting in the full activation of PPARα. The structural basis for the potent effects of pemafibrate on PPARα transcriptional activity predicted by the in silico FMO methods was confirmed by in vitro luciferase assay for mutants. The unique binding mode of pemafibrate reveals a new pattern of nuclear receptor ligand recognition and suggests a novel basis for ligand design, offering cues for improving the binding affinity and selectivity of ligand for better clinical consequences. The findings explain the high affinity and efficacy of pemafibrate, which is expected to be in the clinical use soon.

Comparative Binding Analysis of Dipeptidyl Peptidase IV (DPP-4) with Antidiabetic Drugs - An Ab Initio Fragment Molecular Orbital Study.

Dipeptidyl peptidase IV (DPP-4) enzyme is responsible for the degradation of incretins that stimulates insulin secretion and hence inhibition of DPP-4 becomes an established approach for the treatment of type 2 diabetics. We studied the interaction between DPP-4 and its inhibitor drugs (sitagliptin 1, linagliptin 2, alogliptin 3, and teneligliptin 4) quantitatively by using fragment molecular orbital calculations at the RI-MP2/cc-pVDZ level to analyze the inhibitory activities of the drugs. Apart from having common interactions with key residues, inhibitors encompassing the DPP-4 active site extensively interact widely with the hydrophobic pocket by their hydrophobic inhibitor moieties. The cumulative hydrophobic interaction becomes stronger for these inhibitors and hence linagliptin and teneligliptin have larger interaction energies, and consequently higher inhibitory activities, than their alogliptin and sitagliptin counterparts. Though effective interaction for both 2 and 3 is at [Formula: see text] subsite, 2 has a stronger binding to this subsite interacting with Trp629 and Tyr547 than 3 does. The presence of triazolopiperazine and piperazine moiety in 1 and 4, respectively, provides the interaction to the S2 extensive subsite; however, the latter's superior inhibitory activity is not only due to a relatively tighter binding to the S2 extensive subsite, but also due to the interactions to the S1 subsite. The calculated hydrophobic interfragment interaction energies correlate well with the experimental binding affinities (KD) and inhibitory activities (IC50) of the DPP-4 inhibitors.

Protonation state of F420H2 in the prodrug-activating deazaflavin dependent nitroreductase (Ddn) from Mycobacterium tuberculosis.

The protonation state of the deazaflavin dependent nitroreductase (Ddn) enzyme bound cofactor F420 was investigated using UV-visible spectroscopy and computational simulations. The reduced cofactor F420H2 was determined to be present in its deprotonated state in the holoenzyme form. The mechanistic implications of these findings are discussed.

Electronic spectra of azaindole and its excited state mixing: A symmetry-adapted cluster configuration interaction study.

Electronic structures of azaindole were studied using symmetry-adapted cluster configuration interaction theory utilizing Dunning's cc-pVTZ basis set augmented with appropriate Rydberg spd functions on carbon and nitrogen atoms. The results obtained in the present study show good agreement with the available experimental values. Importantly, and contrary to previous theoretical studies, the excitation energy calculated for the important n-π(∗) state agrees well with the experimental value. A recent study by Pratt and co-workers concluded that significant mixing of π-π(∗) and n-π(∗) states leads to major change in the magnitude and direction of the dipole moment of the upper state vibrational level in the 0,0 + 280 cm(-1) band in the S1←S0 transition when compared to that of the zero-point level of the S1 state. The present study, however, shows that all the four lowest lying excited states, (1)Lb π-π(∗), (1)La π-π(∗), n-π(∗), and π-σ(∗), cross each other in one way or another, and hence, significant state mixing between them is likely. The upper state vibrational level in the 0,0 + 280 cm(-1) band in the S1←S0 transition benefits from this four-state mixing and this can explain the change in magnitude and direction of the dipole moment of the S1 excited vibrational level. This multistate mixing, and especially the involvement of π-σ(∗) state in mixing, could also provide a route for hydrogen atom detachment reactions. The electronic spectra of benzimidazole, a closely related system, were also investigated in the present study.

Energy dissipative photoprotective mechanism of carotenoid spheroidene from the photoreaction center of purple bacteria Rhodobacter sphaeroides.

Carotenoid spheroidene (SPO) functions for photoprotection in the photosynthetic reaction centers (RCs) and effectively dissipates its triplet excitation energy. Sensitized cis-to-trans isomerization was proposed as a possible mechanism for a singlet-triplet energy crossing for the 15,15'-cis-SPO; however, it has been questioned recently. To understand the dissipative photoprotective mechanism of this important SPO and to overcome the existing controversies on this issue, we carried out a theoretical investigation using density functional theory on the possible triplet energy relaxation mechanism through the cis-to-trans isomerization. Together with the earlier experimental observations, the possible mechanism was discussed for the triplet energy relaxation of the 15,15'-cis-SPO. The result shows that complete cis-to-trans isomerization is not necessary. Twisting the C15-C15' bond leads to singlet-triplet energy crossing at ϕ(14,15,15',14') = 77° with an energy 32.5 kJ mol(-1) (7.7 kcal mol(-1)) higher than that of the T1 15,15'-cis minimum. Further exploration of the minimum-energy intersystem crossing (MEISC) point shows that triplet relaxation could occur at a less distorted structure (ϕ = 58.4°) with the energy height of 26.5 KJ mol(-1) (6.3 kcal mol(-1)). Another important reaction coordinate to reach the MEISC point is the bond-length alternation. The model truncation effect, solvent effect, and spin-orbit coupling were also investigated. The singlet-triplet crossing was also investigated for the 13,14-cis stereoisomer and locked-13,14-cis-SPO. We also discussed the origin of the natural selection of the cis over trans isomer in the RC.

(1)La and (1)Lb States of Indole and Azaindole: Is Density Functional Theory Inadequate?

The applicability of time-dependent density functional theory (TD-DFT) is tested in describing (1)La and (1)Lb π-π* states in indole, azaindole, indene, and benzimidazole. Several density functionals including popular three hybrid functionals (B3LYP, PBE0, and mPW1PW91), two meta-GGA functionals (M06-L and M06-2X), and four long-range corrected (CAM-B3LYP, ωB97XD, LC-BLYP, and LC-ωPBE) density functionals have been considered for the present study. The 6-311+G(2d,p) basis set incorporated with two sets of Rydberg sp functions for carbon and nitrogen atoms is utilized. The range-separation parameters for the calculations with the long-range corrected density functionals were tuned by enforcing the DFT version of Koopmans' theorem, and the effect of this tuning on the accuracy of the results is also examined. Results show that all of the hybrid and meta-GGA functionals predict a wrong order of (1)La and (1)Lb π-π* states in indole and azaindole. Although all of the LC functionals correctly predict that (1)Lb is the lowest excited state in indole, the energy gap calculated between the (1)Lb and (1)La state is much smaller than the value observed in the experimental studies. In the case of azaindole, only LC-ωPBE and LC-BLYP functionals could manage to reproduce the correct order of states; however, here too, the calculated energy gap between the two π-π* states is very small compared to the experimental value. Overall, the (1)Lb state excitation energies derived with all of the functionals are overestimated. In contrast, all of the nine selected functionals correctly reproduce the order of states in indene and benzimidazole. The origin of this differing performance is analyzed. Also in the study, oscillator strengths and dipole moments of the excited states are derived, and two other important states, π-σ* and n-π* states, that could play important role in the photochemistry of these molecules are examined.

Is the bisphenol A biradical formed in the pyrolysis of polycarbonate?

An unknown species has been detected in the analysis of the products in a pyrolysis of polycarbonate using Li(+) ion-attachment mass spectrometry (IAMS). The mass spectra exhibited a Li(+) adduct peak at m/z 233 that was tentatively assigned to bisphenol A (BPA) biradical. Experimentally, this assignment was supported by the observation that the production rate increased under an inert nitrogen atmosphere. To further confirm the assignment, the stability of the BPA biradical to intramolecular rearrangement reactions as well as unimolecular decomposition has been analyzed via density functional theory calculations [B3LYP/6-311+G(3df,2p)]. The results show that the bisphenol A biradical is an open-shell biradical singlet that is stable to unimolecular decomposition. Although some of the proposed intramolecular rearrangement products have lower energies than those of the BPA diradical, these pathways have large reaction barriers and the kinetic lifetime of the radical is expected to be of the order of hours under the conditions of the experiment. The calculations also reveal that the bisphenol A diradical has large Li(+) affinities supporting the fact that these Li(+) complexes could be detected in the Li(+) ion attachment mass spectrometry. On the basis of these results the Li(+) adduct peak at m/z 233 detected in the pyrolysis of polycarbonate is assigned to the bisphenol A biradical.

Origin of the unusual ultraviolet absorption of Arsenicin A.

This paper presents a combined experimental and theoretical study of the electronic spectrum of the natural adamantane-type polyarsenical Arsenicin A. Experiments reveal that this molecule strongly absorbs UV light in the absence of an obvious chromophore. The observed absorbance is supported by the time-dependent density functional (TD-DFT) calculations with B3LYP, M06-L, and M06-2X functionals combined with the 6-311+G(3df,2pd) basis set, as well as by symmetry-adapted cluster/configuration interaction (SAC-CI) theory. The theoretical investigations reveal that the absorption is facilitated by through-space and through-bond interactions, between the lone pairs on the arsenic and oxygen atoms and the σ-bonding framework of the molecule, that destabilize occupied and stabilize unoccupied molecular orbitals.

Complete set of critical points on the C60H+ potential energy surface.

To calculate the proton affinity of fullerene (C60), density functional theory was used to determine the global minimum energy structures of both fullerene and its protonated forms. Vibrational frequency calculations were used to check the nature of these predicted structures. In the protonation of C60 in the gas phase, the proton preferentially lies above the carbon atoms at a distance of 1.10 A, which suggests a bond of covalent nature. The proton affinity for fullerene was calculated as 201.8 kcal/mol, compared with the experimental value between 204 and 207 kcal/mol obtained by proton-transfer bracketing studies using Fourier transform mass spectrometry. All five transition states for intramolecular proton transfer in fullerene were found, three for the first time. The activation energy (E(a)) barriers for proton migration were calculated and ranged from 27 to 90 kcal/mol. Different functional groups attached to fullerenes, and their influence on E(a) values are discussed, as are all the possible proton transfers for nonfunctionalized fullerenes.

Electronic transitions in cis- and trans-dichloroethylenes and tetrachloroethylene.

Electronic structures of trans- and cis-dichloroethylenes and tetrachloroethylene were studied using symmetry-adapted cluster configuration interaction theory. Basis sets up to the aug-cc-pVTZ of Dunning, Jr., augmented with appropriate Rydberg functions were used for the calculations. The results derived in the present study show good agreement with the available experimental values. In all cases, the main bright excitation was the pi-->pi( *) transition. The other vertical excitations, pi-->sigma( *), n-->sigma( *), and n-->pi( *), which have not been studied before, were also investigated. First Rydberg series involving transitions from the pi orbitals to one 3s, three 3p, and five 3d orbitals were identified clearly. Several new assignments and reassignments of features in the experimental spectra were suggested. Contrary to earlier prediction, two n-sigma( *) states, along with a pi-sigma( *) state in the dichloroethylenes, were calculated to be located above the main pi-pi( *) state. Accordingly, crossing between both the n-sigma( *) states with the bright pi-pi( *) state is highly likely, unlike conclusions made in the earlier studies. This indicates that the photodissociation mechanism proposed by the earlier calculations warrants revision. Several low-lying triplet excited states were also studied. Electronic spectra of trans-1-chloro-2-fluoroethylene and cis-1-chloro-2-fluoroethylene were also calculated. The pi-->pi( *) transitions of these haloethylenes are compared and interpreted in terms of the inductive and resonance effects.

CCSD calculations on C(14), C(18), and C(22) carbon clusters.

The structure and energetics of the ring isomers of C(4n+2) (n=3-5) carbon clusters were studied by using coupled-cluster singles and doubles excitation theory to overcome the vast differences existing in the literature. The results obtained in the present study clearly indicate that C(14), C(18), and C(22) carbon rings have bond-length and bond-angle alternated acetylenic minimum energy structures. Contrarily, density functional theory calculations were unable to predict these acetylenic-type structures and they ended up with the cumulenic structures. It is found from the coupled-cluster studies that the lowest-energy ring isomer for the first two members of C(4n+2) series is a bond-angle alternated cumulenic D((2n+1)h) symmetry structure while the same for the remaining members is a bond-length and bond-angle alternated C((2n+1)h) symmetry structure. In C(4n+2) carbon rings, Peierls-type distortion, transformation from bond-angle alternated to bond-length alternated minimum energy structures, occurs at C(14) carbon ring.

Electronic excitations of fluoroethylenes.

Several lowest-lying singlet electronic states of vinyl fluoride, trans-, cis-, and 1,1-difluoroethylene, trifluoroethylene, and tetrafluoroethylene were investigated by using symmetry-adapted cluster configuration interaction theory. Basis sets up to Dunning's aug-cc-pVTZ augmented with appropriate Rydberg functions were utilized for the calculations. Calculated excitation energies show a good agreement with the available experimental values. Even in the troublesome pi-->pi(*) transitions, the excitation energies obtained in the present study agree well with the experimental values except in one or two fluoroethylenes. Strong mixing between different states was noticed in a few fluoroethylenes; especially the mixing is very strong between pi-pi(*) and pi-3ppi states in trifluoroethylene. No pure pi-sigma(*) excited state was found in almost all the fluoroethylenes. Several assignments and reassignments of features in the experimental spectra were suggested. The present study does not support the existing argument that the interaction between the pi-pi(*) and sigma-sigma(*) states is the reason behind the blueshift of around 1.25 eV in the pi-pi(*) excitation energy of tetrafluoroethylene. Possible reasons, including structural changes, for this shift are discussed in detail. Several low-lying triplet excited states were also studied.

C4Cl: bent or linear?

The ground state structure for the CCCCCl radical was computed by using symmetry-adapted cluster configuration-interaction (SAC-CI) theory along with density functional theory to overcome the differences raised in the recently published paper [Y. Sumiyoshi et al., Chem. Phys. Lett. 414, 82 (2005)] between the theory and the experiment. SAC-CI results clearly support the earlier experimental conclusion that the radical has the bent ground state structure corresponding to 2Pi symmetry. Contrarily, probably due to spin contamination, mixing of a bent doublet ground state with the quartet components of a linear structure, coupled-cluster singles and doubles (CCSD) calculations were unable to provide reliable results. Results obtained using density functional theory also show that the radical has a bent structure. Some low-lying doublet excited states were also studied using the SAC-CI theory. The energy difference between the ground Pi state and the nearby Sigma state is around 0.2 eV. The excitation energy for the transition with the largest oscillator strength agrees with the strongest absorption peak.

Electronic spectra and photodissociation of vinyl chloride: a symmetry-adapted cluster configuration interaction study.

The vertical absorption spectrum and photodissociation mechanism of vinyl chloride (VC) were studied by using symmetry-adapted cluster configuration interaction theory. The important vertical pi --> pi* excitation was intensively examined with various basis sets up to aug-cc-pVTZ augmented with appropriate Rydberg functions. The excitation energy for pi --> pi* transition obtained in the present study, 6.96 eV, agrees well with the experimental value, 6.7-6.9 eV. Calculated excitation energies along with the oscillator strengths clarify that the main excitation in VC is the pi --> pi* excitation. Contrary to the earlier theoretical reports, the results obtained here support that the C-Cl bond dissociation takes place through the n(Cl-)sigma(C-Cl)* state.

Structural requirements for the interaction of 91 hydroxylated polychlorinated biphenyls with estrogen and thyroid hormone receptors.

Estrogenic and thyroid activities of 91 monohydroxylated PCBs were measured with two-hybrid assays using yeast cells containing the human estrogen receptor ERalpha or human thyroid receptor TRalpha. Estrogenic activity of 30 of the 91 compounds, including all compounds active in the yeast two-hybrid assay, were also measured by a reporter gene assay employing Chinese hamster ovary cells. The mammalian cell assay was more sensitive than the yeast assay but the rank order of estrogenicities of the compounds were in broad agreement for the two assays. Results for estrogenicity and thyroid activity were analyzed by inspection and those for estrogenicity by a theoretical treatment. Inspection indicated para-hydroxyl was more likely to be estrogenically active than meta-, which was more likely to be active than ortho-; one ortho-chlorine was important for activity but additional ortho-chlorines did not increase activity; and 2 lateral chlorines or 2,4,6-chloro- substitution of the non-phenol ring were favorable. In contrast, thyroid activity appeared not to depend strongly on the position of the hydroxyl group although ortho-hydroxyls occurred in the most active compounds. Activity was usually associated with at least one ortho-chlorine, with 2 chlorines in the phenolic ring and, importantly, two chlorines in the non-phenolic ring, and with 1 or 2 chlorines ortho to the hydroxyl group. Examination of the torsion angle between the rings, in the theoretical examination of estrogenicity, suggested that perpendicular orientation (i.e., rigidity) was not essential for activity. Intramolecular hydrogen bonding of the phenolic groups to adjacent chlorines or to the pi-electron cloud of the non-phenol ring possibly decreased activity--the hydroxyl should be free of intramolecular interactions for maximum activity. It was difficult to predict the estrogenic activity of a congener from its obtained potential energy curve (PEC). In general, estrogenically active congeners had large values for the sum of the atomic charges on the carbon atoms of the hydroxylated ring, and on the oxygen atom. Hydroxyl substitution at the para-position allowed the compounds to become more polarizable in the x-axis (molecular axis), whereas OH substitution at the ortho-position made the congeners less polarizable in the same direction. However, no general statement about polarizability and estrogenic activity was possible.

Structure-activity relationships for the toxicity of polychlorinated dibenzofurans: approach through density functional theory-based descriptors.

The applicability of various density functional theory (DFT)-based descriptors--chemical softness, electronegativity, and electrophilicity index--for quantitative structure--activity relationships (QSARs) was investigated for polychlorinated dibenzofurans (PCDFs). The DFT descriptors were obtained by using the three parameter hybrid density functional, B3LYP, with the 6-311G(d,p) basis set. QSARs were developed relating aryl hydrocarbon receptor (AhR) binding affinities, aryl hydrocarbon hydroxylase and ethoxyresorufin O-deethylase induction potencies of PCDFs with DFT descriptors, hydrophobicity, and steric parameters. These QSARs explain around 75% of variation in AhR binding affinities of PCDFs. Congeners with higher toxicity values had larger softness values. Studies also showed that the most toxic isomer of tetrachlorodibenzofurans (TCDFs) and dibenzo-p-dioxins (TCDDs), respectively, had the largest chemical softness value in its respective group. The results show that DFT descriptors could be used as useful electronic descriptors in QSARs for the prediction of toxicity of PCDFs. Overall, 85 congeners of PCDFs and TCDDs were considered in this study.