Toxicity prediction of PHDDs and phenols in the light of nucleic acid bases and DNA base pair interaction

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Highlights

  • Toxicity of a series of toxins (PHDD and PH) of 20 each is explained significantly.

  • A QSTR investigation employing Density Functional Theory is performed.

  • ΔN is quantified through toxins and NA/DNA bases/base pair’s interactions.

  • Global (ΔN) and local (fmax±) are developed as new descriptors in QSTR parlance.

  • ΔN and fmax± explains more than 90% of observed toxicity for the selected toxins.

Abstract

The applicability of Density Functional Theory (DFT) based descriptors for the development of quantitative structure-toxicity relationships (QSTR) is assessed for two different series of toxic aromatic compounds, viz., polyhalogenated dibenzo-p-dioxins (PHDDs) and phenols (PHs). A series of 20 compounds each for PHDDs and PHs with their experimental toxicities (IC50 and IGC50) is chosen in the present study to develop DFT based efficient quantum chemical parameters (QCPs) for explaining the toxin potential of the considered compounds. A systematic analysis to find out the electron donation/acceptance nature of these selected compounds with the considered model biosystems, viz., nucleic acid (NA) bases and DNA base pairs, is performed to identify potential QCPs. Accordingly, PHDDs is found to be electron acceptors whereas phenols as donors, during their interaction with biosystems. Two parameter regression model is carried out comprising global charge transfer (ΔN), and local Fukui Function’s for nucleophilic attack (fk+) for PHDDs and the same for electrophilic attack (fk) in case of PHs. It is heartening to note that our chosen descriptors, viz, charge transfer (ΔN) and Fukui Function (fk±) plays a crucial role by explaining more than 90% of the observed toxic behavior (in terms of correlation-coefficient, R) of PHDDs and PHs. The developed QCPs, viz., ΔN and fk± can be added as the new descriptors in the QSTR parlance.

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The combination of the DFT based global parameter, viz., charge transfer (ΔN) and a local descriptor, viz., Fukui function (fmax±, maximum value) can explain more than 90% of toxicity for polyhalogenated dibenzo-p-dioxins (PHDDs) and phenols (PHs).

Introduction

Attempt to describe the toxic potency of diverse compounds ranging from small molecules to bio-systems through their chemical structural properties has been an important part of the toxicity studies [1], [2], [3]. Biological assays are often limited due to cost, time, safety and sample availability. In this context, it is advantageous to employ quantitative structure-activity relationship (QSAR) [4], [5] methods. A successful QSAR study can predict the biological activity or relative toxicity of diverse class of chemical compounds. At the same time, it is possible to predict new ligands (compounds or drug molecules) [4], [5] with ease when compared to experimental studies.

In QSAR parlance, an immense number of descriptors to explain the toxic potency are used in the literature [1], [2], [3]. The QSAR descriptors are usually based on the geometrical parameters (e.g., distance to atom, gravitational index, moment of inertia etc.) [6], [7], topology (e.g., atomic degree, bonds to atom, connectivity index, Wiener numbers, Zagreb index etc.) [8], [9], electronic properties (e.g., Atomic polarizability, atomic valence, partial π charge, partial σ charge etc.) [10] or quantum mechanics (e.g., electronic energy, heat of formation, ionization energy, electron affinity, molecular dipole moment, molecular polarizability, Electronegativity (χ) etc.) [11], [12]. Recently, researchers have found few quantum chemical parameters, e.g., electrophhilicity index (ω) [13], philicity (ωκα; α = +,- at kth atomic site) [14], quantum dissimilarity (Δωij) [15] etc. to quantify toxic potential of various compounds.

Polyhalogenated dibenzo-p-dioxins (PHDDs) are the important chemicals of concern because of their elevated concentrations, wide distribution and toxicity. Biochemical and pathological studies on aquatic organisms have consistently revealed that the lateral substituted congeners are more potent than the non-lateral congeners [16], [17], [18]. The marine aquatic contamination leads to increased concentration of these toxic compounds in sea-fish and others. The edible varieties accumulate the toxicities in different cells and produce contaminated fish oils and products and subsequent health hazards, instead of health benefits of uptake. Further, accumulation of these health hazardous toxic products may lead to various diseases including increased incidence of carcinogenesis particularly involving urinary bladder and other organs [16]. The origin of toxicity of PHDDs in living cells has been attributed to the electron accepting nature in charge transfer complex with a receptor [19]. Hence, electron affinity of PHDDs is used as an important quantity in understanding their toxic effects. Due to their extreme toxicity and the existence of many isomers, experimental investigations on toxic PHDDs are difficult and hence a careful quantitative structure-toxicity relationships (QSTR) study is required for this purpose. A number of structure-toxicity studies have been performed [20], [21], [22], [23], [24], [25] to predict/explain the toxicity of the polyaromatic hydrocarbons (PAH) class of chemicals, e.g., Polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs) and polyhalogenated dibenzo-p-dioxins (PHDDs) etc. using various structural descriptors like hydrophobicity constant [20], [21], 13C NMR data [22], 3D-CoMFA analysis [23], [24] etc. Also the concentration dependent effect of several PCB, PHDD and PCDF congeners as antiestrogens were determined in the aryl hydrocarbon (Ah)-responsive MCF-7 human breast cancer cell lines [25]. The toxicity of PCDDs/PHDDs to DNA has been noticed through a number of studies, e.g., Roy and Wirgin [26] have reported that PAHs, PCDDs/Fs and PCBs are found to elicit significant DNA damage in Microgadus tomcod. FAO/WHO consultation, Switzerland [27] has reported that PCDDs are constituted as highly toxic and can cause chromosomal aberrations, micronuclei sister chromatid exchange in mammalian cells in absence of metabolic activation. Loprieno et al. [28] have reported that TCDD is found to cause chromosomal abnormalities (or aberration) of bone marrow cells of mature, male albino mice. Magdy and co-workers [29] have reported that a significant decrease in quantitative levels of DNA and RNA is noticed in all PCDD treated animal testes (with mature male albino mice) comparing with control has been found.

On the other hand, Phenol (hydroxybenzene) is a colorless, crystalline organic solvent which is considered to be very harmful ecotoxins and they possess carcinogenic, cytotoxic and teratogenic properties [30]. The activities of the chemical, petrol or pharmaceutical industries are one of the major reasons for the existence of phenols in the environment. Phenols may also be formed through natural processes, e.g., formation of phenol and p-cresol during decomposition of organic matter or synthesis of chlorinated phenols by fungi and plants [31]. Toxicity of phenol is associated through two main processes, one is unspecified toxicity related with hydrophobocity of the individual compound and the second one is the formation of free radicals [32]. The ecotoxicity of phenols family towards living beings is a serious concern now a day.

In this work, a sincere attempt is made to explore the uses of density functional theory [33], [34] bases reactivity descriptors to investigate the structure-toxicity relationship in the series of polyhalogenated dibenzo-p-dioxins (PHDDs) and phenols (PHs). For this purpose, the experimental toxicity data for PHDDs are utilized in terms of the negative of the logarithm of molar concentration of chemical necessary to displace 50% of radiolabled tetrachloro dibenzo-p-dioxin (TCDD) from the Ah receptor in rat lever (pIC50) [24]. On the other hand, in case of PHs, toxicity values are considered in terms of 50% inhibitory growth concentration (IGC50) against a teardrop-shaped, unicellular, ciliated freshwater protozoan (about 50 μm long), Tetrahymena pyriformis. A number of QSTR studies have been performed on PHDDs [20], [21], [22], [23], [24], [25] and PHs [35], [36], [37] in which some of the reported parameters are noticed to be useful. For example, Cronin et al. [36] have developed a couple of electrophilic parameters, viz., energy of the lowest unoccupied molecular orbital (ELUMO) and maximum acceptor superdelocalizability (Amax) along with 1-octanol/water partition coefficient (log P) to explain toxicity of a large number of aromatic compounds with correlation (R2) range 48–78%. Chattaraj and co-workers [38], [39], [40] have developed a quantum chemical descriptor, viz., electrophilicity index (ω) which is found reasonable to describe toxicity of various aromatic toxins. However, the field deserves lot more efforts for identification of significant and scientifically justified descriptors for the betterment of explaining toxicity of PHDDs and PHs inhibitors. The present work is an effort along that direction.

The genesis of toxicity is supposed to be governed by the possible charge transfer between a toxin and a bio-system [38], [39], [40]. Since it is expected that a toxin usually prefer to interact directly/indirectly with nucleic acid (NA) bases and DNA base pairs, in the present study, we have chosen a model biosystem comprising five nucleic acid (NA) bases, viz., adenine, thymine, guanine, cytosine and uracil along with two DNA base pairs, viz., GCWC and ATH. The amount of charge transfer (ΔN) between a toxin and nucleic acid bases/DNA base pairs are calculated to gain insights into the origin of toxicity vis-à-vis the charge transfer between a toxin and biosystem. Also, Fukui function (FF) [41], [42] is very well known dimensionless local descriptor to take care on reactivity at any atomic site of a molecule. In this line, a sincere effort is tendered for identification of the couple of such potential parameters: a global descriptor, viz., electron transfer (ΔN) and a local parameter, viz., Fukui function (FF) [41], [42]. Experimental toxicities (pIC50 and pIGC50) for both the PHDDs and PHs are correlated with their corresponding calculated values determined by two parameter (ΔN and FF) regression analysis resulting more than 90% prediction of toxic potential of both the PHDD and PH series of compounds.

Section snippets

Theoretical method

The ionization potential (IP) and electron affinity (EA) can be expressed in terms of the highest occupied (∈HOMO) and the lowest unoccupied (∈LUMO) molecular orbital energies using Koopmans’ approximation [33] as,IP=HOMO;EA=LUMO

In density functional theory, the chemical potential (μ) is defined as [33],μ=(δEδρ)v(r)where E, ρ(r) and v(r) are the total energy, electron density and external potential respectively.

Using the finite difference approximation μ can be expressed in terms of I

Computational details

The geometries of all the toxins, viz., polyhalogenated dibenzo-p-dioxins (PHDDs) and phenols (PHs) as well as the model biomolecules, viz., NA bases and DNA base pairs are optimized using 6-31G[d] basis set in the framework of B3LYP theory which comprises Becke's three-parameter hybrid exchange [52] and LYP correlation functionals [53]. All calculations are performed using the GAUSSIAN 09 [54] suites of programs. The Fukui function for all the PHDDs and PHs molecules are obtained using

Results and discussion

The structural templates of PHDDs with required atom numbering and the list of phenol compounds (PHs) are presented in Table 1, Table 2 respectively, along with the identity (ID) of the molecules. The electron accepting/donating nature of the PHDDs and PHs are analyzed by their interaction with biomolecules employing the ΔN descriptor. The model bio-system considered in the present study comprising five nucleic acid (NA) bases, viz., adenine, thymine, guanine, cytosine and uracil along with two

Concluding remarks

In the present work, experimental biological toxicities of polyhalogenated dibenzo-p-dioxins (PHDDs) and phenols (PHs) are correlated with their corresponding calculated/predicted values (pIC50 and pIGC50 respectively), employing QSAR based regression analysis using the combination of a global parameter, viz., charge transfer (ΔN) and a local descriptor, viz., Fukui function (fmax±, maximum value). The present study reveals that PHDDs behave as electron acceptors whereas PHs are found to be

Acknowledgements

SMR is thankful to CSIR, New Delhi for Research Associate ship (Grant No. 09/1007(0003)/2013-EMR-I). DRR is thankful to the SERB (DST), New Delhi, Govt. of India, for financial support by awarding FAST Track project grant (D.O. SR/FTP/PS-199/2011).

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