Quantum Computational, Spectroscopy Investigation (FTIR, FT-Raman), HOMO-LUMO and Docking Studies on Selegiline

B. Aysha Rifana^1,2, Shyam Sundar¹, Johanan Christian Prasana^1,2*, A. Anuradha^2,3

¹Department of Physics, Madras Christian College, East Tambaram, Chennai 600059, Tamil Nadu, India

²University of Madras, Chennai, 600005, Tamil Nadu, India

³PG & Research Department of Physics, Queen Mary’s College, Chennai 600004, Tamil Nadu, India

^*Correspondence to: Johanan Christian Prasana

Citation: Rifana BA, Sundar S, Prasana JC, Anuradha A (2022) Quantum Computational, Spectroscopy Investigation (FTIR, FT-Raman), HOMO-LUMO and Docking Studies on Selegiline. Sci Academique 3(2): 44-49

Received: 20 September, 2022; Accepted: 04 October 2022; Publication: 08 October 2022

Abstract

Computational analysis has been a powerful tool in characterizing a compound. With its high precision, accurate results can be obtained for any given compound. Density Functional Theory, a quantum mechanical computational method was used to study vibrational spectra of the title compound. Relative and absolute values of FTIR and FT-Raman were found. Potential energy distribution percentage for each vibrational mode was calculated. The calculated HOMO and LUMO energies were -6.1022 eV and -0.4493 eV, respectively, resulting in a band gap energy of 5.6529 eV, indicating charge transfer within the molecule. UV spectra of the title compound were observed by TD-DFT method. Electron localization function (ELF), Localized orbital locator (LOL), Molecular electrostatic potential (MEP) of the title compound were also obtained. Drug likeness values were analyzed to assess the title compound’s potential as an active pharmaceutical component. Biological nature of the compound was observed by molecular docking studies.

Introduction

Monoamine oxidase (MAO), discovered by Balschko in the 1930s, is one of the most important enzymes in neurotransmitter metabolism [1]. MAO has the potential to be used in the treatment of several neurodegenerative diseases, including Parkinson’s and Alzheimer’s. MAO-catalyzed reactions generate hydrogen peroxide, a source of hydroxyl radicals, and MAO inhibitors may thus be useful in managing the outcome of stroke and other tissue damage caused by oxidative stress [2]. Selegiline (title compound) was developed in Hungary by Knoll et al. in 1964 as a novel monoamine oxidase (MAO)-inhibitor antidepressant. In patients with early Parkinson’s disease (PD), Selegiline postpones the need for levodopa therapy [3]. From the deprenyl and tocopherol antioxidative treatment, selegiline, with or without tocopherol, reduces physical and psychological deficits in patients with PD within first month of treatment and reduces the probability of reaching a primary endpoint, the decision to treat with levodopa [4]. The empirical formula of selegiline is C13H17N, and IUPAC name is ethyl (2R)-N-methyl-1-Phenyl-N-prop-2-ynylpropan-2-amine.

According to literature survey, a few spectroscopic and in vitro assays have already been published on the title compound [5,6]. The present study provides a complete vibrational, electronic and topological analysis under theoretical background. This paper describes a comprehensive spectroscopic investigation of the title compound at the B3LYP/6-311++G (d, p) level of theory. Frontier molecular orbitals (HOMO, LUMO) determine how the molecule interacts with other species, allowing us to characterize the chemical reactivity of the molecule. MEP (Molecular Electrostatic potential), ELF (Electron localization function) and LOL (Localized orbital locator) were used to examine the distribution of electrons and reactive sites on the surface of the title compound. Drug likeness were also carried out. Molecular docking analysis is performed by selecting suitable protein targets to study the bio activeness of the title compound.

Computational Details

The molecular parameters of the title compound in ground state were calculated using DFT B3LYP/6-311++G (d, p) basis set. In DFT methods, Becke’s three(B3) combined with Lee, Yang and Parr(LYP) method is the best predicting results for molecular geometry and vibrational wave numbers for moderately larger molecule [7,8]. Chemcraft 1.8 [9] was used to visualize optimized geometrical structure of the title compound. Vibrational assignment calculations in terms of PED contributions were performed with high accuracy using VEDA software. [10]. Molecular electrostatic potential (MEP) and HOMO-LUMO studies were carried out using Gauss View 5.0software [11-13]. Localized Orbital Locator (LOL) and Electron Localization Function (ELF) two-dimensional plots were obtained using MULTIWFN 3.4.1 [14]. Swiss ADME Tool is used to determine the drug likeness nature and ADME properties of the title compound [15]. The binding energy, inhibition constant, and other biological parameters of ligand-protein interaction were determined using the AutoDock 4.2.1 programme [16].

Results and Discussion

Molecular Geometry

Bond parameters (bond angle and bond length) of the title compound were obtained by DFT/B3LYP method with basis set 6-311++G (d, p). The optimized geometrical structure is shown in Fig. 1. Bond angle, the angle between three atoms and bond length, the distance between two neighboring atoms values obtained were tabulated in table 1. Homonuclear atoms such as C12-C15, C15-C17 and C6-C12 have the highest bond lengths of 1.553 Å, 1.532 Å and 1.513 Å. On the other hand, heteronuclear atoms such as C15-N21, N21-C26 and N21-C22 have the highest bond lengths of 1.483 Å,1.470 Å and 1.463 Å. Least bond length values were found in atoms C30-H3, C3-H9 and C1-H7 of values 1.063,1.084 and 1.085. In the case of bond angle, the maximum values obtained were 121.3°, 121.1° and 121.1° which corresponded to the atoms C1-C6-C12, C4-C5-C6 and C2-C1-C6 respectively. Presence of benzene ring structure comprised of atoms C1 to C6 was observed in the title compound.

Figure 1: Optimised geometric structure of (2R)-N-methyl-1-Phenyl-N-prop-2-ynylpropan-2-amine.

Table 1: Geometrical parameters Bond Length (Å) and Bond Angle (°) optimized in (2R)-N-methyl-1-Phenyl-N-prop-2-ynylpropan-2-amine with basis set 6-311++G (d, p).

Vibrational Analysis

Vibrational analysis of the title compound was carried out in detail through FT-IR and FT-RAMAN studies. For a non-linear compound, the title compound will have n = 3N-6 normal vibrational modes, i.e., n = 87. The contribution of vibrational frequency by a particular set towards the potential energy were represented as potential energy distribution (PED%) and their values are tabulated in table 2 [17]. A factor of 0.961 was multiplies to the unscaled frequency values to get the scaled values as they are more refined and accurate. Types of vibration such as stretching, bending and torsional were given by the vibrational assignment. All vibrational calculations were carried out by GAUSSIAN 09W with basis set, B3LYP/6-311++G (d, p). fig.2 and fig.3 represents the theoretical FT-IR and FT-RAMAN spectra.

C-H Vibration

Heteroaromatic organic compound and its derivatives commonly exhibit multiple peaks in the region 3100 to 3000 cm^-1 [18,19]. The C-H stretching bands of the title compound was reported in the range 3340 to 2773 cm^-1. The highest Stretching 98% was observed in the vibrational region of 2911 cm^-1 and 2693 cm^-1. Pure stretching was not found in any region.

C-C Vibration

The bonds between 1650 and 140 cm^-1 range in the aromatic and heteroaromatic compounds are assigned to carbon-carbon vibration [20]. In the present study, Theoretical frequencies assigned to C-C stretching vibrations are 2131 cm^-1,1591 cm^-1 and maximum PED contribution to this vibration is 96%.

C-N Vibration

Mixing of several modes is possible in the region makes the documentation of C-N bonds very difficult. Frequency nearer to 1500 cm^-1 indicates C=N bonds while frequency nearer to 1300 cm^-1 indicates the presence of C-N bonds [21]. For the title compound, C-N stretching vibrations were found at 1201 ,1127 ,1041 ,974, 914 and 777 cm^-1.

Figure 2: FT-IR Spectra.

Figure 3: FT-RAMAN Spectra.

Table 2: Theoretical vibrational spectroscopic data with vibrational assignments for title compound using DFT B3LYP/6-311++G (d, p) basis set.

Frontier Molecular Orbital

Frontier molecular analysis was carried out for the title compound using DFT method along with B3LYP/6-311++G (d, p) to understand the interactions of the molecule with other molecules. Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) is derived from FMO analysis. Transition between HOMO whose energy is less as they are at ground state to LUMO whose energy levels are high as they constitute excited states gives us the values of Energy Band Gap (eV) shown in fig. 4 [22,23]. Whilst Homo are electron donors, the LUMO is more electronegative in nature. High electron affinities values denote that the molecular interactions are strong. Electronegativity deals with the tendency of the molecule to accept more electrons. The energy gap between two states plays a vital role as many other parameters such as electron affinity, ionization potential, chemical softness and are tabulated in table 4. Chemical softness and chemical hardness were found to be 0.17689 η and 2.8265 S. HOMO and LUMO values characterizes the chemical kinetics stability of the title compound. For shorter energy gaps, the compound is polarized, and they are called as soft molecules [24].

Table 4: Calculated energies values of the title compound.

Figure 4: The molecular orbitals and energies for HOMO and LUMO of ethyl (2R)-N-methyl-1-phenyl-N-prop-2-ynylpropan-2-amine

UV – Visible Spectral Analysis

UV spectrum of the title compound was obtained from GAUSSUM software. Time dependent DFT was carried out to visualise the effect of solvent to aqueous phase of the title compound. The study was carried out in solvent phase in solvent model density (SDM). Through the computational method, the values of maximum wavelength λ_max (nm), Band gap energy(eV), excitation energy (cm^-1), and oscillator strength (f) of the title compound were obtained and tabulated in table 5 [25]. The band gap was calculated using the formula E = hc/λ. UV spectral analysis show the electronic absorption which excites the atom from highest occupied molecular orbital (HOMO) to lowest unoccupied molecular orbital (LUMO). This energy gap (5.0371eV) between the two molecular orbitals agreed with the energy band gap (5.6529eV) calculated from FMO [26]. Fig .5 Shows theoretical UV–vis spectrum of the title compound.

Table 5: Theoretically calculated electronic properties using the TD-DFT method.

Figure 5: theoretical UV–vis spectrum of the title compound

Molecular Electrostatic Potential

The distribution of charges over a 3-dimensional space creates an electrostatic potential around it. MEP also known as molecular electrostatic potential explains us about how the molecule would react to charges surrounding it. The mapping of MEP was done with DFT methods along with basis set B3LYP/6-311++G (d, p) [27]. There are two major sites in a molecule namely electrophilic sites wherein the atoms in this region have tendency to attract electrons and nucleophilic sites wherein the atoms in this region are ready to share electrons. MEP diagram is shown in Fig.6. The colour region varies from red to blue where red signifies electrophilic site and blue signifies nucleophilic site. Potential in the current study ranges from – 4.002e^-2 eV to 4.002e^-2 eV. From the figure, the red region denotes electrophilic region which is due to the presence of N21 atom [28,29]. The blue region at the borders constitutes nucleophilic sites. H atoms occupying this region are nucleophilic in nature. The green site in map indicates neutral sites.

Figure 6: The MEP map of the title compund.

Electron Localization Function & Local Orbital Locator

Topological analyses of ELF and LOL were carried out using MULTIWFN software [30]. The 2D mappedELF and LOL is shown in fig. 7 and fig. 8. The colour codes vary from 0.001 to 1.000. High ELF values are represented by red region whilst low ELF values are represented by blue region [31]. The main objective to perform ELF studies is to understand quantitative behaviour of electrons in a system. The difference in kinetic energy density contributes towards Pauli repulsion on two like spin electrons which attributes towards the behaviour of the electron. The red region indicates high Pauli repulsion, and blue region indicates low Pauli repulsion [32]. Several colours are represented on this surface. For the title compound, blue colour circle in 2d structure, indicates the presence of a depletion region between valence shell and inner shell.

Figure 7: The 2-D mapped ELF for the title compound.

The red orange region depicts strong electronic localisation [33,34]. Localized orbital locator is like that of ELF. The hydrogen and carbon regions have minimum values of LOL. The LOL has colour codes ranging from 0.000 to 0.800 [35]. The white region encircled with red region of H19 atom indicates that there is an excess of electron cloud which exceeds the covalent region.

Figure 8: The 2-D mapped LOL for the title compound.

Drug Likeness

The canonical smile of selegiline was taken from PubChem [36]. Using this, Drug likeness parameters tabulated in table 8 was obtained by SwissADME software [37]. The acceptable values of HBA and HBD should be less than 5 and 10 respectively, which is 1 and 0 for the title compound. The MlogP parameter gives an idea about lipophilic character of the molecule, which is 3.25 for the title compound. This is in the acceptable range as it is less than 4.15. The number of rotatable bonds should be less than 10 and is 4 in this case. Based on the analysis, the title compound satisfies Lipinski’s rule of five most likely favourable to be subjected to any desired studies since it proves that it is an active drug. [38]

Table 8: Descriptors and corresponding values for drug likeness of the title compound.

Molecular Docking

Molecular docking of the title compound was carried out using AutoDock software. Protein used for docking was taken from protein data bank (PDB). Optimised docked structure of target protein with the title compound is shown in fig. 9. Protein had a resolution of 2.30 Å [39]. Protein structure was obtained from RCSB PDB format. Auto dock tool (ADT), a graphical user interface was used to obtain binding energy of the title compound to a receptor. The title compound was selected to be docked into the active site of protein 4f1t (Parkinson’s disease). Docking parameters such as Bond distance (Å), Inhibition constant (μm), Intermolecular energy (kcal/mol), Binding Energy (kcal\mol) and Reference RMSD (Å) are tabulated in table 7. Minimum binding energy of – 3.61 kcal/mol and intermolecular energy of −4.8 kcal/mol have been observed in the interaction which interprets that protein and the title compound has strong bond between them. Inhibition constant and bond distance found to be 2.27 μm and 2.631 Ǻ respectively [40].

Figure 9: Optimised docked structure of the target protein with the title compound.

Table 7: Docking parameters of the protein 4f1t with the title compound.

Conclusion

In the present work, a detailed Spectroscopic (FT-IR, FT-RAMAN), UV, FMO, Reactive site analysis (MEP, ELF, LOL) along with molecular docking studies on the title compound, Selegiline has been reported. Optimized molecular geometry was obtained using DFT method along with basis set B3LYP/6-311++G (d, p). The complete vibrational assignments and calculations of potential energy distribution (PED) were carried out using Veda software. Reactive sites of the title compound were determined using LOL and ELF. From MEP diagram, the electrophilic and nucleophilic sites were identified. Electronic properties of the compound were studied theoretically using TD-DFT method. Energy gap calculated from UV spectrum was in good agreement with HOMO-LUMO energy gap. Finally, molecular docking analysis was carried out for protein 4flt associated with Parkinson’s disease and showed binding affinity value of -3.61 kcal/mol.

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