Original Article revista.iq.unesp.br | Vol. 47 | n. 3 | 2022 | 39 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 Experimental, DFT study, and in silico molecular docking investigations of dichlorodiphenyltrichloroethane against human estrogen receptor alpha Tabe Ntui Ntui1 , Vincent Ndem Osabor2 , Peter Amba Neji1 , Michael Akomaye Akpe2 , John Akwagiobe Agwupuye2+ , Stephen Adie Adalikwu3 , Terkumbur Emmanuel Gber2 , Bitrus Hyelavalada Andrew2 , Uduak Ugbaja2 1. Cross River University of Technology, Faculty of Physical Sciences, Calabar, Nigeria. 2. University of Calabar-Nigeria, Department of Pure and Applied Chemistry, Calabar, Nigeria. 3. Cross River State College of Education, Akamkpa. +Corresponding author: John Akwagiobe Agwupuye, Phone: +2348100056340, Email address: agwupuye.john@yahoo.com ARTICLE INFO Article history: Received: November 09, 2021 Accepted: May 07, 2022 Published: July 01, 2022 Section Editor: Assis Vicente Benedetti Keywords 1. DFT 2. molecular docking 3. DDT 4. estrogen receptor ABSTRACT: Advanced computational tools allowed to study a pure commercial sample of dichlorodiphenyltrichloroethane (DDT) prepared in liquid phase in KBr pellets and characterized using FT- IR and GC-MS followed by the application of DDT for molecular docking against human estrogen receptor alpha. The compound was modelled using GaussView software. Using Veda 04 program, the theoretical vibrational energy distributions and experimental vibrational frequencies were compared. Interestingly, C1 and C2 possess the highest atomic charge density distribution (ACDD) of -0.284e and -0.283e while C21 and C11 have lowest ACDD of -0.064e and -0.063e in a relative manner, since the deactivating power of chlorine atoms decreases charge densities of the bonded carbon. The highest intramolecular interacting perturbation energy is 1121.92 kJ mol–1 occurs between π*C19–C21 donor orbital and π*C14–C16 acceptor orbital while the least intramolecular interaction occurs in the lone pair of LPC26 and the sigma nonbonding (𝜎C1–Cl24) NBO orbitals with E(2) of 32.21 kJ mol–1. Steric interaction was the only interaction found within the complex after the docking. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 mailto:agwupuye.john@yahoo.com https://orcid.org/0000-0001-8413-9373 https://orcid.org/0000-0002-4249-8578 https://orcid.org/0000-0003-4034-5057 https://orcid.org/0000-0001-7258-7427 https://orcid.org/0000-0002-1798-1058 https://orcid.org/0000-0003-1320-9260 https://orcid.org/0000-0002-1901-3675 https://orcid.org/0000-0001-9778-796X https://orcid.org/0000-0003-3822-2795 Original Article revista.iq.unesp.br 40 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 1. Introduction Experimental and density functional theory (DFT) studies of the powerful insecticide dichlorodiphenyltrichloroethane (DDT), often referred to as 41, 41 – DDT have been carried out by several researchers, and studies showed that it has great impact on human health and environment in general. The DDT is one of the organochlorine pesticides (OCPs) with the potential to contaminate or pollute water and other environmental matrices due to its toxic effect on human and aquatic organisms (Buah-Kwofie et al., 2018; Miao et al., 2020). Notwithstanding, the persistent nature of DDT in water is due to its feeble solubility and excess half-life and the flimsy soluble nature of DDT in water results in their deposition on soil, which may either spread to the surface water or affect the groundwater. Besides, when aquatic invertebrates are subjected to DDT, it has the potential to disturb the function of the endocrine system of fishes and birds that consume them (Kowenje et al., 2013; Sruthi et al., 2017). R. Zhang et al. (2021) studied the detoxifying mechanism of 1-chloro-4-[2, 2, 2-trichloro-1-(4- chlorophenyl) ethyl] benzene metabolized by human P450 enzymes using a combination of molecular dynamic, quantum mechanics/molecular mechanics and DFT. Their fact-findings reveals that DDT can be broken-down by P450 enzymes through the hydrogen abstraction and electrophilic addition mechanism, and the primary derivatives are epoxides (2, 3-oxide-DDT and 3, 4-oxide-DDT), DDE and dicofol. Similarly, Iramain et al. (2020) carried out a combine experimental (Fourier Transform Infrared (FT-IR) and Fourier Transform Raman (FT-Raman) and different DFT methodologies (B3LYP/6-31G+(d) and B3LYP/6-311++G(d, p)) studies to structurally characterized the potent insecticide dichlorodiphenyltrichloroethane (4′, 4′-DDT). Furthermore, DFT technique at the Becke-86 exchange functional and LeeYang–Parr correlation functional under generalized gradient approximation methods was used in inspecting the chemiresistive detecting potential of a buckled configuration of antimonene nanotube (SbNT) towards the water pollutants–DDT and toxaphene (Bhuvaneswari et al., 2020). The DFT calculations were carried out using B3LYP/6-31G (d) basic sets. The experimental and theoretical results for the vibrational frequency analysis were reported. The energies of the frontier molecular orbitals (FMOs) involving the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were analyzed with tabular and graphical representation. Fukui functions, chemical reactivity descriptors, natural bond orbital (NBO), electrostatic potential, and a comparison between three population analysis; MPA, NPA and atomic dipole moment corrected Hirshfeld (ADCH) were calculated and reported to reveal the most reactive sites in the compound and its overall reactivity. 2. Methodology 2.1 Experimental method A pure commercial sample of liquid DDT was prepared in potassium bromide (KBr) pellets and used to study experimental FT-IR spectrum using KBr disc at wavenumber region 4000-650 cm–1 with a CARY 630 FTIR–Agilent technology spectrophotometer and with a spectral resolution at 8 cm–1. Similarly, electrospray ionization mass spectroscopy (ESI-MS) was employed for further structural determination of DDT. 2.2 Computational method The initial structure of l,l,l,2-tetrachloro-2,2-bis(p- chlorophenyl)ethane (DDT) was modeled using GaussView software (Fig. 1) according to the single X- ray crystal structure obtained by Hovmöller et al. (1978). Geometry optimization of DDT were performed using B3LYP which includes Becke’s (B3) parameter exchange functional along with Lee–Yang Parr’s (LYP) gradient corrected correlation functional (Lee et al., 1988) using Gaussian 09 and GaussView 6.0.16 softwares (Dennington et al., 2016; Frisch et al., 2009). Pregeometry optimization using the molecular mechanic optimization with molecular mechanics in combination with forcefield implemented in the HyperChem program (HyperChem, 2001) has been performed on model structures and outputs used for further geometry optimization at the B3LYP/6- 31+G(d,p) level of theory. Natural bond orbital analyses were calculated by the NBO 3.1 module embedded in Gaussian. In the calculation, a 6- 31+G(d,p) basis set was used for the investigation, using water solvation model as an implicit approach. The QTAIM investigations and all other wavefunction analyses were conducted by Multiwfn 3.7 dev, which is a multifunctional wavefunction analysis program developed by Lu and Chen (2012). Unless otherwise specified, the default settings were used throughout these calculations. All molecular electrostatic isosurface maps were rendered by visual molecular dynamic (VMD) 1.9.3 program (Humphrey et al., 1996) based on the outputs of Multiwfn analyzer. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 Original article revista.iq.unesp.br 41 Eclética Química Journal, vol. 47, n. 2, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 Figure 1. HOMO-LUMO of the tile molecule. Source: Elaborated by the authors, obtained using Visual molecular dynamic (VMD) 1.9.3 program based on the outputs of Multiwfn analyzer. 3. Results and discussion 3.1 Structural analysis 3.1.1 Fourier transform infrared vibrational analysis The vibrational modes associated with relevant and specific molecular structures of the calculated compound in question have been the main goal of the vibrational analysis. From the vibrational analysis carried out, the maximum number of possibly active noticeable fundamentals of a nonlinear molecule that contains N atoms is equal to (3N-6) usual modes of vibration (Agwupuye et al., 2021a). The studied compound has 36 atoms and 102 modes of vibrations. Out of the 102 modes of vibration, 35 are stretching modes, 34 are bending modes, and 33 are torsional. The DFT computed vibration wavenumber are often of much magnitude as compared to the experimentally determined wave number owing to the DFT basic set deficiencies and the combination of electron correlation effects. Hence, factors called scale factors are used to fit the DFT computed wave numbers compared to the observed ones for accurate results fitting. The scale factor used is less than one (0.96) to reduce the overall deviation. The fundamental modes in terms of vibrational assignments associated with theoretical IR and potential energy distributions computed with the DFTB3LYP/6-311++G(d,p) method along with investigational FT-IR spectrum presented in Tab. S1 and Fig. S1 of the supporting information respectively. Few bands with weak intensity were not present in the spectra which can be confirmed by theoretically computed FT-IR intensity values. 𝑪−𝑪𝒍 vibrations: The characteristic R-NH2 vibrations for primary amines have been assigned in the region 3500–3200 cm–1 (Pretsch et al., 2013). Bend in primary amines results in a broadband in the range 1640–1560 cm–1 (Pretsch et al., 2013). The present calculations place the R-NH2 stretching modes at 3451 and 3358 cm–1 in experimental FT-IR. The H– N–H band was also observed experimentally to occur at 1640 cm–1. The bands at 3516 and 3417 cm–1 for R- NH2 stretch and 1628 cm–1 for N-H bond B3LYP/6- 31++G(d,p) set are in good agreement with observed spectral data. These are intense stretching modes and identified from the PED in Tab. 1. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p53-54 https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p53-54 Original Article revista.iq.unesp.br 42 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 Table 1. Detailed assignments of fundamental experimental and theoretical vibrations of AATCo by normal mode analysis. Theoretical Value Mode No. Experimental IR (cm–1) Unscaled Frequency Scaled Frequency 𝑰𝑰𝑹 𝒃 Assignments with 𝑃𝐸𝐷𝑑(%) 1 3239 3235 3106 2.10 𝑣CH(98) 2 800 869 801 100.22 𝑣 ClC(42)+ 𝑣 ClC(49) 6 3229 3100 4.10 𝑣CH(84) 7 3220 3091 6.28 𝑣CH(95) 8 3216 3087 27.29 𝑣CH(84) 9 3206 3078 37.66 𝑣𝑎𝑠𝑦CH(88) 10 3193 3065 14.70 𝑣CH(89) 11 3183 3056 23.77 𝑣CH(88) 12 3183 3056 5.87 𝑣CH(88) 13 3180 3053 17.90 𝑣CH(97) 14 2214 2316 2223 124.98 𝑣𝑎𝑠𝑦(90)+𝑣CC(10) 18 1655 1589 2.85 𝑣CC(51)+𝛽HCC(20) 19 1636 1571 1.61 𝑣CC(53)+𝛽HCC(13) 20 1607 1620 1555 16.61 𝑣CC(53)+𝛽HCC(10) 21 1574 1511 35.87 𝑣CC(14)+𝑣𝑎𝑠𝑦 CC(12)+𝛽′ HCC(29) 22 1559 1497 283.54 𝑣𝑎𝑠𝑦CC(38)+𝛽′ HCC(29) 23 1533 1472 15.54 𝛽HCC(52)+𝛽CCC(11) 31 1366 1311 1311 𝑣𝑎𝑠𝑦(52)+𝛽HCC(18) 32 1349 1295 3.83 𝛽HCC(56) 33 1340 1286 6.88 𝑣CC(39)+𝛽HCC(25) 37 1226 1177 49.48 𝑣𝑎𝑠𝑦CC(20)+𝛽HCC(71) 38 1190 1142 0.79 𝛽HCC(79) 39 1186 1139 0.35 𝛽′ HCC(84) 45 1049 1007 3.47 𝑣CC(46)+𝛽HCC(24)+𝛽CCC(17) 46 1032 991 0.15 𝛽HCC(11)+𝛽CCC(70) 47 1015 974 0.13 𝑣CC(27)+𝛽CCC(57) 49 979 940 0.06 𝜏HCCC(81) 53 940 902 3.85 𝜏HCCC(83) 64 703 675 25.25 𝜏HCCC(27)+𝜏HCCC(13)+𝜏RCCCC(40) 65 694 666 2.87 𝛿CCCC(25)+𝜏RCCCC(25)+𝜏RCCCC(13)+𝛿CCC(15) 66 690 654 628 1.41 𝛽CCC(63)+𝛽CCC(12) 67 630 605 0.12 𝛽CCC(84) 73 534 513 21.23 𝛽CCC(28) 81 421 404 1.41 𝜏HCCC(13)+𝜏RCCCC(67) 82 419 402 6.33 𝜏RCCCC(69) 89 274 263 7.34 𝑣CC(19)+𝛽CCC(16) 96 115 110 0.83 𝛿CCCC(18) 97 83 80 2.98 𝛽CCC(10)+𝛽CCS(10)+𝛽CCC(14)+𝜏CCCC(10) 98 64 61 4.58 𝜏RCCCC(63) 99 61 59 3.30 𝜏RCCCC(55)+𝛿CCCC(65) v = symmetrical stretching; vasy = asymmetrical stretching; β = in plane bending; δ = out of plane bending; τ = torsional; τR = torsional ring. Source: Elaborated by the authors using data obtained from a CARY 630 FTIR–Agilent technology spectrophotometer and Gaussian 09/ GaussView 6.0 software. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 Original article revista.iq.unesp.br 43 Eclética Química Journal, vol. 47, n. 2, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 =𝑪−𝑯 vibrations: The C–H stretching vibration modes in the aromatic ring was observed at range 3300–3000 cm–1 region (Bassey et al., 2022). The title compound observes =C–H stretching vibrational mode at 3239 cm–1 for experimental FT-IR while the computational frequency of the title compound was observed at 3106 cm–1. These are intense stretching modes and identified from the PED. 𝑪−𝑪 and 𝑪=𝑪 vibrations: The aromatic 𝐶=𝐶 and 𝐶−𝐶 stretching vibrations (aromatic ring stretching vibrations) arises in the region 1625–1400 cm–1 (Tadesse, 2017). In the present study, the observed C=C stretching vibrational modes of the title compound are 1607 and 1506 cm–1 in experimental FT- IR and also C–C stretching vibrational modes are assigned at 1297 and 1181 cm–1 respectively in experimental FTIR. The C–C–C the range 999– 665 cm–1 was reported for planar vibration wave number by Saminathan et al. (2021). The experimental aromatic ring C–C–C bending vibrations of the title compound has appeared at 731 and 690 cm–1 in experimental FT-IR. The computationally calculated FT-IR for C=C stretching vibrations, C–C stretching vibrations, and aromatic ring C–C–C bending vibrations are 1602 and 1411, 1286 and 1190, 763 and 688 cm–1 respectively. 3.1.2 Electron spray ionization-mass spectrometry analysis The ESI-MS is a high-speed and accurate spectroscopic technique used in the qualitative and quantitative identification of small organic molecules and the determination of their component molecular weights. The ESI-mass spectrum of DDT is presented in Fig. S1 of the supporting information, the peaks with higher intensity at m/z are 42.0, 125.0, 81.0, 152.0 and 170.0 and they correspond to the species C2H4N, C5H5N2S, C4HS, C7H8N2S and C11H10N2. The peaks with low intensity at m/z are 53.0, 68.0, 97.0, 108.0 and 137.0. Their corresponding species are [C2S]+, C5H8, C5H5S, N2C4S and C6H5N2S. 3.2 Frontier Molecular Orbital (FMO) The can be linked on two important parameters in quantum chemistry—HOMO and LUMO. These parameters are very important in the analysis of the reactivity and the kinetic stability of a molecule (Agwupuye et al., 2021b). Within the molecule, the electron donating capability can be seeing in the HOMO, while the ability of an atom or molecule to accept electrons is indicated by the LUMO. The difference between these two parameters, which are HOMO and LUMO energies (EHOMO – ELUMO) match to the energy gap of the molecule. The bond gap depicts information which indicate the structure’s stability and intramolecular interaction as a result of charge transfer from the donor and acceptor atom (Khalid et al., 2020). Using Gauss View 6.0.16 software, the values of the EHOMO, ELUMO and energy gap were obtained maximizing the used with the output log file gotten from the free optimized structure. The computed FMO and global reactivity descriptors are reported in Tab. 2. Using the Multiwfn analyzer for calculating the HOMO-LUMO orbital compositions, the results revealed that the HOMO orbitals are majorly distributed within C4, C11, C14, and C21 ring atoms with compositions of 13.10, 10.84, 12.75, and 11.43% respectively. However, the LUMO molecular orbital compositions are primarily situated on C1, Cl25, Cl24, and Cl26 atoms respectively. The HOMO-LUMO molecular orbital distributions are reported in Fig. 1. Table 2. HOMO-LUMO energy. S/No B3LYP/6-31+G(d) Values 1 Etotal –2839.87 a.u. 2 Dipole moment 1.04 Debye 3 EHOMO –6.71 eV 4 ELUMO –1.48 eV 5 Egap 5.23 eV 6 EHOMO−1 –7.12 eV 7 ELUMO+1 –0.89 eV 8 E(HOMO−1) − E(LUMO+1) 6.23 eV 9 μ 4.09 10 η 2.62 11 ω 3.20 12 S 0.19 13 𝜒 –4.09 Source: Elaborated by the authors, calculated using B3LP/6- 31G(d) in Gaussian 09 software. 3.3 Natural Bond Orbital Analysis The NBO provides a profitable technique in understanding the computational solutions of the Schrödinger equation, it also provided the convenient basis for studying the charge transfer or conjugate interaction in the molecules especially the nature of hydrogen bonding and also interaction among bonds (Agwupuye et al., 2021b). This parameter is very significant in studying the interactions of donor and acceptor orbitals of molecules that enables the understanding of intra- and intermolecular bonding and https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p53-54 Original Article revista.iq.unesp.br 44 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 interactions. Donor occupied orbitals can interact strongly (Suresh et al., 2014). Second-order perturbation Fock matrix was carried out to study the Lewis valence orbital (donor) i, non-Lewis valence orbital (acceptor) j, interactions in the NBO basis. The stabilization energy associated with the electron delocalization between Lewis (filled) and non-Lewis (unfilled) is estimated in Eq. 1 (Armaković et al., 2012; Enudi et al., 2021). 𝐸(2) = ∆𝐸𝑖,𝑗 = 𝑞𝑖 𝐹2(𝑖,𝑗) 𝜀𝑖−𝜀𝑗 (1) From the equation above, the donor orbital occupancy was represented by qi the donor orbital occupancy, 휀𝑖 and 휀𝑗 represent the diagonal elements, and the Fock matrix elements were represented by F(i,j). The larger perturbation energy value also called the stabilization energy value E(2) depicts a stronger interaction between electron donors and electron acceptors, i.e., the greater extent of conjugation of the whole system and the more donating tendency from the electron donors to electron acceptor was vividly understood by this analysis. NBO analysis of the studied structure has been performed by using the DFT/B3LYP/6- 311+G(d) level of theory (Agwupuye et al., 2021c) to understand clearly the charge transfer or conjugative interaction, delocalization of electron density in the molecule and energy of interaction as reported in Tab. 3. From the results, the highest intramolecular interacting perturbation energy is 1122 kJ mol–1 occurring between π*C19 – C21 donor orbital and π*C14 – C16 acceptor orbital while the least intramolecular interaction is observed to occur in the lone pair of πpC26 and the sigma nonbonding (𝜎C1 – Cl24) NBO orbitals having E(2) energy of 32 kJ mol–1. Table 3. NBO second order perturbation energies for the studied compound. S/NO Donor Acceptor 𝑬(𝟐)(kcal mol–1) 𝑬(𝒊) − 𝑬(𝒋) 𝑭(𝒊, 𝒋) 1 π*C19 – C21 π*C14 – C16 268.21 0.01 0.094 2 π*C9 – C11 π*C4 – C6 255.27 0.01 0.084 3 π*C19 – C21 π*C15 – C17 218.48 0.01 0.800 4 π*C9 – C11 π*C5 – C7 184.74 0.01 0.079 5 π*C14 – C16 π*C19 – C21 21.57 0.27 0.069 6 π*C15 – C17 π*C19 – C21 20.49 0.27 0.067 7 π*C19 – C21 π*C15 – C17 19.58 0.30 0.068 8 π*C19 – C21 π*C14 – C16 18.99 0.30 0.067 9 πpCl28 π*C9 – C11 12.28 0.33 0.062 10 πpC26 𝜎C1 – Cl24 7.70 0.39 0.043 Source: Elaborated by the authors, calculated using NBO 3.1 module embedded in Gaussian 09 software. 3.4 Population Analysis DFT study of atomic charge is very important analysis in describing the distribution and location of ionic charges within the molecule thereby predicting the individual atomic reactivity. This is very relevant in many areas of studies as it stretches across the field of quantum chemistry and molecular modeling, details of electrostatic interaction with molecular force fields can also be provided by this analysis (Agwupuye et al., 2021a) Using Mulliken Population Analysis (MPA), the atomic charges of the studied DDT in this present study are obtained, Hirshfeld (HPA), Atomic dipole moment corrected Hirshfeld (ADCH), and Becke (BPA) methods. The computational population result for the charge distributions for the different methods is presented in Fig. 2. It is observed that C1 and C2 possess the highest atomic charge density distribution of -0.284 and -0.283e while C21 and C11 are less with atomic charge distribution of -0.064 and -0.063e respectively. This is caused by the electron withdrawing power of the chlorine atoms resulting in decreasing in charge densities of the bonded carbon. Figure 2. Population analysis plot. Source: Elaborated by the authors, plotted using multiwfn analyzer software. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 Original Article revista.iq.unesp.br 45 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 3.5 Absorption Study The excitation type, energy, wavelength, oscillator strength, and major orbital contributions in both gas and solvents are presented in Tabs. 4 and 5 respectively. The studied compound has vertical excitation energies of 5.34 and 5.37 eV with associated wavelengths of 232 and 230 nm in gas and solvents respectively. In the gas phase, the prominent intense absorption (of 21.39% orbital contributions) arises as a result of electronic transitions from HOMO (89) → LUMO+2 (91) molecular orbital. It can also be deduced that the electron density is uniformly distributed throughout within the LUMO in the molecule, as the result of the electron withdrawing moiety it is shifted towards the LUMO and LUMO+2 transition accordingly. Table 4. Excitation energies and oscillator strength in solvation. Excitation type E/eV λ(nm) f Major contributions Assignment SO→S1 5.3436 232.02 0.0104 89 →91 (21.39%) π → π* 86 →92 (11.49%) 89 →92 (10.05%) S0→S2 5.3601 231.31 0.0107 89 →93 (20.00%) π → π* 89 →90 (17.02%) 89 →92 (10.88%) S0→S3 5.6127 220.90 0.3030 89 →90 (71.58%) π → π* 89 →93 (5.40%) 88 →92 (3.15%) S0→S4 6.0123 206.22 0.1097 88 →90 (45.09%) π → π* 89 →94 (11.36%) 89 →92 (11.03%) S0→S5 6.1582 201.33 0.0537 89 →91 (26.72%) π → π* 85 →90 (14.31%) 89 →92 (10.08%) Source: Elaborated by the authors, calculated using DFT/B3LYP/6- 311+G(d). In the solvents, a similar transition is involved between HOMO → LUMO+2 molecular orbitals with an oscillator strength of 0.0207. Other LUMO orbitals having different vertical excitations in solvents are LUMO+3 and LUMO+5 having orbital contributions of 12.66 and 12.93% respectively. For all the ground state (S0) to the fifth singlet states (S1), S0 → S1 first vertical singlet states transition has the highest orbital contributions in solvents involving HOMO-2 to LUMO orbitals. Table 5. Excitation energies and oscillator strength in solvation. Excitation type E/eV λ(nm) f Major contributions Assignment S0→S1 5.3730 230.75 0.0207 89 →91 (13.18%) π → π* 89 →92 (12.66%) 89 →94 (12.93%) S0→S2 5.3794 230.48 0.0150 87 →90 (100.46%) π → π* 89 →93 (16.56%) 88 →92 (9.31%) S0→S3 5.5677 222.69 0.3205 89 →90 (70.20%) π → π* 88 →92 (4.00%) 89 →94 (3.71%) S0→S4 5.9995 206.66 0.1320 88 →90 (47.5859) π → π* 89 →92 (10.30%) 88 →91 (6.76%) S0→S5 6.1053 203.07 0.1008 89 →92 (44.37%) π → π* 89 →90 (10.82%) 89 →92 (5.35%) Source: Elaborated by the authors, calculated using multiwfn software. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 Original Article revista.iq.unesp.br 46 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 3.6 Molecular Electrostatic Potential Molecular electrostatic potential diagrams are primarily used to show the electron density distribution difference in a compound. In the title molecule, electron density is evident around the DDT ring without any significant distortion. The distance of these electrons apart is also indicated as can be seen in Fig. 3. 3.7 Density of States Density-of-state (DOS) is essentially the number of different states at a particular energy level that electrons are allowed to occupy, and it is very vital in this kind of study to appropriately characterized orbital composition by visualizing them. In the underlying curves, the plots show the different energy levels in unit energy interval at the number of molecular orbitals. Multiwfn analyzer was used in plotting the total DOS (TDOS) map for the title molecule with contribution from different sets of molecular orbitals (Fig. 4) (Liu et al., 2020) and the prominent curves are denoted by the colored peaks. Figure 3. Molecular electrostatic potential map of the title molecule. Source: Elaborated by the authors. Isosurface maps were rendered by visual molecular dynamic (VMD) 1.9.3 program based on the outputs of Multiwfn analyzer. Figure 4. Density of states plot for DDT. Source: Elaborated by the authors, plotted using Multiwfn analyzer software. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 Original Article revista.iq.unesp.br 47 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 3.8 Nonlinear optics Nonlinear response of properties like amplitude, phase, frequency and other propagation features of incident fields were clearly explained by nonlinear optics. The interaction of applied electromagnetic radiation to produce new fields form incidents one coins the term nonlinear optical effects (Ray, 2010). The growth of nonlinear optical materials has attracted important attention in fundamental and applied research. Nonlinear optical materials have vast applications in technologies such as in the design of information storage, processing of signal, switching of optical and design of optoelectronic devices in modern communication technology (Y. Zhang and Wang, 2017). Highly delocalized 𝜋 − electron parts in a molecule and also high electron donors and acceptors containing organic materials are very good sources of nonlinear optical materials (Prasad and Ulrich, 2012). Taylor’s series expansion of the total dipole moment, 𝜇𝑡𝑜𝑡 induced by the field is used to present the NLO response of an isolated molecule in an electric field (𝜔) Eq. 2. 𝜇𝑖(𝐸𝑖) = 𝜇𝑖 + 𝑎𝑖𝑗𝐸𝑗 + 1 2! 𝛽𝑖𝑗𝑘𝐸𝑗𝐸𝑘 + 1 3! 𝛾𝑖𝑗𝑘𝑙𝐸𝑗𝐸𝑘𝐸𝑙 + ⋯ (2) where, 𝐸𝑖 is the homogenous electric field, 𝜇𝑖(𝐸) is known as the dipole moment in an electric field, 𝜇𝑖 is refers to dipole moments at zero field, 𝛼𝑖𝑗, 𝛽𝑖𝑗𝑘, 𝛾𝑖𝑗𝑘𝑙 are the polarizability tensor component, first-order hyperpolarizability component, and second-order hyperpolarizability component respectively. Using the x, y, and z components, electric dipole moment (𝜇) (Eq. 3) and the average polarizability (𝛼𝑡𝑜𝑡) (Eq. 4) can be obtained as: 𝜇 = √(𝜇𝑥 2 + 𝜇𝑦 2 + 𝜇𝑧 2 (3) 𝛼𝑡𝑜𝑡 = 𝛼𝑥𝑥+𝛼𝑦𝑦+𝛼𝑧𝑧 3 (4) Anisotropy of polarizability, Eq. 5. ∆𝛼 = 2 – 1 2⁄ [(𝛼𝑥𝑥 − 𝛼𝑦𝑦) 2 + (𝛼𝑦𝑦 − 𝛼𝑧𝑧) 2 + (𝛼𝑧𝑧 − 𝛼𝑥𝑥)2] 1 2⁄ (5) The first order polarizability (𝛽𝑖𝑗𝑘) is a 3rd rank tensor (3 × 3 × 3 matrix). The magnitude of the first order hyperpolarizability i is calculated using the Eq. 6. 𝛽𝑡𝑜𝑡 = √𝛽1 2 + 𝛽2 2 + 𝛽3 2 (6) Where, beta is given by Eq. 7: 𝛽𝑖 = 1 3 ∑ (𝛽𝑖𝑗𝑗 + 𝛽𝑗𝑖𝑗 + 𝛽𝑗𝑗𝑖)3 𝑗=1 (7) = ∑ 𝛽𝑖𝑗𝑗 3 𝑗=1 Here i, j = x, y, and z. and the final form resulting from Kleinman symmetry (Isborn et al, 2007). The calculations were carried out by incorporating polar keyword and B3LYP functional and 6 – 311 + G(d) basis set and the output was loaded lunching multiwave function analyzer where the results obtained and presented in Tab. 6. Table 6. The electric dipole moment (𝜇), polarizability (∆𝛼), and first order hyper polarizability (𝛽) of reduced compound by B3LYP/6-311+G(d,p) approach and Multi wave function analyzer. Parameter Value μx 0.355 μy –0.204 μz –0.002 μTotal 0.410 Parameter Value αxx 171.175 αxy 11.897 αyy 159.84 αxz 0.811 αyz 2.334 αzz 255.023 αTotal 88.786 ∆μTotal 537.319 Parameter Value βxxx –26.884 βxxy –11.862 βxyy –65.056 βyyy –165.703 βxxz 2.624 βxyz 17.599 βyyz 52.314 βxzz –1355.432 βyzz –355.432 βzzz 87.982 βTotal 597.706 Source: Elaborated by the authors, calculated using B3LYP/6-311+G(d,p) and Multiwfn analyzer. 3.9 Molecular docking studies Molecular docking studies were carried out using human estrogen receptor alpha for human X-ray https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 Original Article revista.iq.unesp.br 48 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 structures (1R5K, 1ERR, 2BJ4 and 3ERT) cocrystallized with DDT. The structure of the compound was drawn using Gassian 09 (Glendening et al., 2018). The optimize structure of the compound was use in Multiwfn (Lu, 2017) to invoke the different atomic number in order to know the specific atoms that interacted with the deferent amino acid. The main purpose of molecular docking is to obtain an optimized conformation for each of the drug and protein with relative orientation between them such that the free energy of the overall system is minimized (Mascarenhas and Ghoshal, 2008). It is a computational tools and techniques employed in predicting and evaluating the suitability of the studied compounds as drug candidate. It is a method that analysis the orientation and conformation of molecules into the binding site of a macromolecular targe. Toward this objective, comparative molecular docking was employed to study the drug delivery of human estrogen receptor alpha for human X-ray against DDT. The receptor proteins were prepared by removing water molecule, adding explicit hydrogens, charges and correction of deformation in amino acid sequence. The active sites of the receptor protein were predicted and defined based on the interaction of the crystallographic ligand and the complexes with the receptor molecules respectively as visualized with the discovery studio visualizer. This aims at predicting the type of interactions and the docking procedure also aims to identify and recognize the correct and most favorable binding poses within the binding site of the studied protein (Pagadala et al., 2017). From these docking results hydrogen bonding was not the only bonding type that exists in the studied compounds, other interaction like unfavorable Donor–Donor bond, pi cation, pi sigma, pi alkyl, salt bridge and other as can be seen in 2D and 3D plots. However, for each receptor interaction with DDT the highest pose was recorded as –34, –26, –25 and –32 kJ mol–1 for 1ERR-DDT, 1R5K- DDT, 2BJ4-DDT and 3ERT respectively. These interactions are shown in Fig. 5a and 5b from this docking result, it can be seen that DDT interaction with 1ERR have the highest binding affinity compared to other receptors. The 3D structure of the hERα within the receptor backbone is presented in Fig. 5b. This steric effect that was observed in the docking result is due to the constituent atoms that make up the molecule occupy some degree of space, and when atoms come too close together there’s a rise in the energy of the molecule due to the atoms being forced to occupy the same physical space. This explains why steric effect can have a dramatic effect on the observed or preferred shape of a molecule and in some cases even its chemical reactivity (Barnes, 2019; Yang et al., 2010). The docking results of the DDT 1ERR, 1R5K, 2BJ4 and 3ERT as well as the root means square distance in reference to the first mode are presented in Tab. 7. Table 7. Binding affinities and root mean square distance of the docking score. Receptors Binding affinity (kJ mol-1) Rmsd (I.b) Rmsd (u.b) 1ERR –33.9 2.448 5.061 1R5K –25.9 2.122 3.872 2BJ4 –25.1 1.169 5.252 3ERT –32.2 1.297 4.858 Source: Elaborated by the authors, calculated using autoDoc Vina tools. https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 Original Article revista.iq.unesp.br 49 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 Figure 5. Showing 3D, steric interactions and other forms of interaction of the human estrogen receptor alpha X- ray structures as cocrystallized with DDT. Source: Elaborated by the authors, Generated using AutoDoc Vina tools. 4. Conclusions High level quantum computational tools were used to study a pure commercial sample of DDT prepared in liquid phase in KBr pellets and characterized using FT- IR and GC-MS followed by the application of the title molecule for molecular docking against human estrogen receptor alpha (hERα). Using water model as an implicit approach, the high calculations were computed using a 6 – 31 + G(d,p) basic set. The fundamental modes in terms of vibrational assignments associated with theoretical IR and potential energy distributions were computed by the use the DFT- B3LYP/6-311++G(d,p) basic sets along with experimental FT-IR spectrum. It was observed that bands with weak intensity were not existing in the https://revista.iq.unesp.br/index.php/ecletica https://doi.org/10.26850/1678-4618eqj.v47.3.2022.p39-52 Original Article revista.iq.unesp.br 50 Eclética Química Journal, vol. 47, n. 3, 2022, 39-52 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v47.3.2022.p39-52 spectra, and this was confirmed with theoretically calculated FT-IR intensity values. Using Multiwfn analyzer for calculating the HOMO-LUMO orbital compositions, the results revealed that the HOMO orbitals are majorly distributed within C4, C11, C14, and C21 ring atoms with compositions of 13.10, 10.84, 12.75, and 11.43% respectively. However, the LUMO molecular orbital compositions are primarily situated on C1, Cl25, Cl24, and Cl26 atoms respectively. From the NBO result, the highest intramolecular interacting perturbation energy is 1122 kJ/mol occurring between π*C19 – C21 donor orbital and π*C14 – C16 acceptor orbital while the least intramolecular interaction is observed to occur in the lone pair of electron from πpC26 and the sigma nonbonding (𝜎C1 – Cl24) NBO orbitals having 𝐸(2) energy of 32 kJ/mol. ADCH analysis shows that C1 and C2 possess the highest atomic charge density distribution of –0.284 and – 0.283e while C21 and C11 are less with atomic charge distribution of –0.064 and –0.063e accordingly. The electron withdrawing power of chlorine atoms in the molecules was observed to be the cause of this changes resulting in decreasing in charge densities of the bonded carbon. And in the adsorption studies, all the ground state (S0) to the fifth singlet states (S1), S0→S1 first vertical singlet states transition has the highest orbital contributions in solvents involving HOMO-2 to LUMO orbitals. While in the molecular docking studies, steric interaction was the only observable interaction that was found within the complex after the docking however, there were no observable hydrogen interactions between the drug (DDT) and any of the hERα, which would have been the bases for determining the drug activeness with the receptors. Authors’ contribution Conceptualization: Tabe N. Ntui, John A. Agwupuye, Terkumbur E. Gber Data curation: Stephen A. Adalikwu, Michael A. Akpe Formal Analysis: John A. Agwupuye Funding acquisition: Uduak Ugbaja, Tabe N. Ntui, Michael A. Akpe Investigation: Bitrus H Andrew, Terkumbur E. Gber, John A. Agwupuye Methodology: John A. Agwupuye, Tabe N. Ntui Project administration: Vincent N. Osabor, Peter A. Neji, John A. Agwupuye Resources: Michael A. Akpe, Stephen A. Adalikwu. Software: Terkumbur E. Gber, John A. Agwupuye Supervision: Tabe N. Ntui, Vincent N. Osabor, Peter A. Neji Validation: John A. Agwupuye, Terkumbur E. Gber Visualization: John A. Agwupuye Writing – original draft: Terkumbur E. Gber Writing – review & editing: John A. Agwupuye Data availability statement GC-MS, FT-IR analysis was carried at Central Laboratory at Usman Dan Fodio University, Sokoto – Nigeria and the DFT analysis was coducted using Gaussian 09, GaussView 6.0.16, and multiwfn 3.7 softwares. Funding Not applicable. Acknowledgments Tabe Ntui is very thankful to his Supervisor, Dr. Peter Neji and Hitler Louis for his immense support and contributions. References Agwupuye, J. A.; Louis, H.; Enudi, O. C.; Unimuke, T. O.; Edim, M. M. Theoretical insight into electronic and molecular properties of halogenated (F, Cl, Br) and hetero- atom (N, O, S) doped cyclooctane. Mater. Chem. Phys. 2021a, 275, 125239. https://doi.org/10.1016/j.matchemphys.2021.125239 Agwupuye, J. A.; Louis, H.; Unimuke, T. O.; David, P.; Ubana, E. I.; Moshood, Y. L. 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