key: cord-0986275-5dtksv1n
authors: Rizwana B., Fathima; Muthu, S.; Prasana, Johanan Christian; Abraham, Christina Susan; Raja, M.
title: Spectroscopic (FT-IR, FT-Raman) investigation, topology (ESP, ELF, LOL) analyses, charge transfer excitation and molecular docking (dengue, HCV) studies on ribavirin
date: 2018-12-31
journal: Chemical Data Collections
DOI: 10.1016/j.cdc.2018.09.003
sha: c5f536a2266e119e70b92537123efcfb612d7004
doc_id: 986275
cord_uid: 5dtksv1n

Abstract Ribavirin, a triazole derivative has a wide application in the medical field as an antiviral drug. In the present work, a quantum chemical approach was followed to study the vibrational modes and the reactivity. Experimental techniques of FT-IR, FT-Raman were used to study the vibrational spectrum. A complete vibrational analysis was carried out and assignments of the fundamental modes were proposed. Molecular electrostatic potential, frontier molecular orbitals, electronic localization function and fukui functions were analyzed by using wavefunction analyser, Multiwfn 3.4.1 to study the chemical reactivity. Band gap energy of the title molecule is found to be 6.01 eV, as calculated from the HOMO-LUMO energies. The intermolecular charge transfer within the molecule was confirmed from the charge transfer interactions. Molecular docking studies were carried out to study the biological activity of the compound. Viral target proteins such as Dengue and Hepatitis C were chosen and the respective docking parameters were calculated.

Owing to their interesting physiological properties, a decent number of five membered aromatic systems having three heteroatoms at symmetrical positions have been studied. The presence of three nitrogens in triazole provides an interesting class of compounds. Triazole and its derivatives exhibit a broad spectrum of pharmacological properties such as antibacterial and antifungal activities [1] and also there are a lot of reports on the interaction between triazole and metal in preventing corrosion of metals [2] [3] [4] [5] . Although triazole and its derivatives show a wide spectrum of activity, the literature search revealed that not much has been reported about the structure/activity relationship of this class of compounds. An ab-initio method has been followed to study the derivatives of triazoles [6] [7] [8] . Since the first report of the broad spectrum antiviral activity and synthesis of ribavirin [9, 10] , the in vitro and in vivo antiviral activity has been confirmed in many independent laboratories [11] [12] [13] [14] [15] [16] [17] . Ribavirin has been proved clinically effective against hepatitis A virus [18] [19] [20] . Synthesis and determination of antiviral activity of the 2 (3 )-O-Methyl derivatives of Ribavirin [21] , of some phosphates of ribavirin [22] and amino acid esters of ribavirin were discussed in detail [23] .

To the best of our knowledge, no detailed spectroscopic investigation has been made on the title compound. This motivates to provide a complete vibrational spectroscopic investigation on the molecule to give a detailed assignment of the fundamental bands in FTIR and FT Raman spectra on the basis of calculated PED. The present study provides a complete vibrational and electronic analysis under both theoretical and experimental background. A complete spectroscopic investigation of the title compound using B3LYP/6-311 ++ G(d,p) level of the theory has been reported in this work. In this attempt, the vibrational analysis has been performed to screen the physical and chemical properties of the present compound using computational calculations using Density Functional Theory. The distribution of electrons and the reactive sites on the surface of the title compound were analysed using ESP (Electrostatic potential), ELF (Electron localization function) and LOL (Localized orbital locator). The charge transfer within the molecule was identified and frontier molecular orbitals were plotted. The local reactivity descriptors like the local softness and Fukui function were obtained. Molecular docking studies were performed to identify the antiviral activity of the title compound on a couple of viral protein.

Ribavirin was purchased from Sigma Aldrich Company with 99% purity and was used as such without any further purification. The FTIR spectrum of the title compound was recorded using a KBr pellet technique in the region 40 0 0-40 0 cm −1 in the evacuation mode with 1.0 cm −1 resolution on a PERKIN ELMER FTIR spectrophotometer. The FT Raman spectrum of the title molecule was recorded in the region 40 0 0-10 0 cm −1 in a pure mode using Nd:YAG Laser of 100 mW with 2 cm −1 resolution on a BRUCKER RFS 27 at IIT SAIF, Chennai, India.

Becke3-Lee-Yang-Parr (B3LYP) [24] level with 6-311 ++ G(d,p) basis set using Gaussian 09 W [25] program package was employed for all the theoretical computations. Using the Gaussian 09 W software the spectroscopic profiling of the title molecule was carried out in its optimised state. VEDA [26] program enabled percentage potential energy distribution (PED) analysis. In addition, the relative Raman intensities were attained from the scattering activities of the fundamental modes [27, 28] . Electrostatic potential (ESP) on molecular vdW (vander Waal) surface is a useful guide to the molecule's reactive behavior, especially in noncovalent interactions [29] . ELF and LOL are tools for performing covalent bonding analysis, as they reveal regions of molecular space where the probability of finding an electron pair is high [30, 31] . The Fukui functions are electron density-based local reactivity descriptors, proposed to explain the chemical selectivity or reactivity at a particular site of a chemical system [32] . The analyses such as ESP, Molecular orbitals, Fukui functions, ELF and LOL were finished by Multiwfn 3.4.1 [33] , which is a multifunctional wavefunction analysis program. The ESP map was rendered by VMD 1.9.1 program [34] based on the outputs of Multiwfn. Frontier molecular orbitals were plotted and the charge transfer interactions were studied. NBO analysis gives a clear evidence of stabilization originating from hyperconjugation of various intramolecular interactions. The reactive sites of the title compound were identified by calculating the Fukui functions for all the atomic sites. AutoDock Suite 4.2.1 [35] was used to find the minimum binding energy, inhibition constant and various parameters of the ligand-protein docking interactions [36] .

The optimized molecular structure of the title compound with the numbering scheme of the atoms is shown in Fig. 1 .

The bond parameters such as bond lengths and bond angles obtained from Gaussian software. From the single crystal XRD data [37] , it is found that the title compound belongs to the crystal system orthorhombic with P212121 space group and the cell dimensions are as follows; a = 14.863 Å ; b = 7.512 Å ; c = 8.788 Å . The results are compared with the experimental X-ray diffraction data [33] of the title compound and are listed in Table 1 . 

The maximum number of potentially active observable fundamentals of the non-linear molecule is 3N-6, where N is the number of atoms present in the molecule [38] . The title molecule consists of 29 atoms, which has 81 normal modes of vibration. The theoretical and experimental FT-IR and FT-Raman spectra are shown in Figs. 2 and 3 while the spectral assignments along with PED contributions are tabulated in Table 2 . The O -H stretching vibrations for organic compounds are expected to arise in the range 3380 ± 200 cm −1 [39] . For the title compound, the O -H stretching appears at 3719, 3658 and 3637 cm −1 as pure stretching mode as evident from PED value of 100%, 98% and 98% in DFT-B3LYP method and it is in good agreement with the experimental wavenumbers at 3723, 3670, 3630 cm −1 and 3720, 3640 cm −1 in FT Raman and FT-IR spectrum respectively. The asymmetric and symmetric stretching NH 2 vibrations of the title compound were theoretically calculated at 3599 and 3466 cm −1 respectively with a PED 99%. The corresponding wavenumbers were observed at 3460 cm −1 in FT-Raman and 3450 cm −1 in FT-IR spectrum. The NH 2 bending vibration [40] was observed at 1555 cm −1 theoretically and was found to occur at 1560 and 1550 cm −1 in FT-Raman and FT-IR spectrum respectively with 82% of PED. The characteristic carbonyl (C = O) stretching vibrations of the IR and Raman spectra occur in the region of 1725 ± 65 cm −1 [41] . The C = O stretching vibration for the title compound was found at 1712 cm −1 theoretically and can be seen at 1710 and 1720 cm −1 in FT-Raman and FT-IR spectrum respectively. An average frequency shift of 700 cm −1 is 

The ESP-mapped along with surface extrema of the title compound is shown in Fig. 4 and the graph of surface area plotted against different ESP ranges is shown in Fig. 5 . Green and orange spheres represent surface local minima and maxima of ESP respectively. Global minimum on the surface was found to be −42.97 kcal/mol, its large negative value is owing to the lone pair of oxygen O7. The global maximum arising from the positively charged H29, the ESP at this point is much larger (55.32 kcal/mol) than that at other. This is because of the presence of oxygen, which attracted a great deal of electrons from H29. From the Fig. 5 , it can be seen that there is a large portion of the molecular surface having small ESP value, namely from −20 to 30 kcal/mol. The regions above and below the triazole ring have an abundant π -electron cloud thus corresponding to the negative part; the positive part mainly arises from the positive charged C -H hydrogens; the near-neutral part represents the border area between the negative and positive parts. There are also small areas having remarkable positive and negative ESP value, corresponding to the regions closed to the global ESP minimum and maximum, respectively.

The topological analyses of the electron localization function (ELF) and the localized orbital locator (LOL) were completed using Multiwfn program. Color shade maps and contour maps of the ELF and LOL for the title molecule are presented in figures. From the Fig. 6 , it can be seen that the covalent regions have high LOL value (red regions), the electron depletion regions between valence shell and inner shell are shown by the blue circles around nuclei. A lone pair of oxygen O7 atom is pointed out by purple arrow. A similar picture is seen from the ELF map, the regions around C3, N4, C6 where found to have lesser value where electrons are expected to be delocalized. Whereas the regions around the hydrogen atoms have comparatively large values indicate bonding and nonbonding localized electron. In general, a large ELF or LOL value [31] in a region indicates high localization of electrons, due to the presence of a covalent bond, a lone pair of electrons, or a nuclear shell in that region.

The 3D plots of the HOMOs and LUMOs of the title compound generated using the Multiwfn program from the Gaussian output using B3LYP/6-311 ++ G(d,p) as the basis set are shown in Fig. 7 . The band gap energy value of the title molecule calculated from the HOMO-LUMO energies was 6.0146 eV, which confirms that the molecule has a stable structure and the band gap energy value was comparable to the band gap energy value of the bioactive molecules [43, 44] . Table 3 , presents the HOMO energy, LUMO energy, energy gap, few reactivity descriptors. The HOMO and LUMO values are related to the ionization potential (IP) and electron affinity (EA) of the molecule. The IP value indicates that the energy value of 7.3851 eV is required to remove an electron from the HOMO. The lower value of EA (1.3705 eV) indicates that the title compound readily accepts electrons to form bonds.

To bring out a correlation between the HOMO-LUMO gap and charge transfer, the charge transfer within the molecule due to excitation has been studied. Multiwfn [33] program was used to investigate and visualize the charge transfer due to the excitation. The time dependent DFT (TD-DFT) calculations were made on the title compound using B3LYP/6-311 ++ G(d,p) as the basis set. The diagrams representing the electron-hole (green-blue) distribution and the electron-hole overlap for the 3 excited states are shown in Fig. 8 . Table 4 indicates the values of overlap of electron-hole distribution (S), charge transfer length (D), r and excitation energy (E) for different excitation modes. The distance between the centroid of hole and electron is a measure of charge transfer length (D); the larger the value, the longer length the charge transfers. Charge-transfer excitation (CT) occurs when the spatial separation of hole and electron is large which lead to movement of charge density from one place to another place. From the table, it can be seen that the charge transfer length of the second excitation mode is comparatively larger and r is also higher for the same mode indicating the fact that the second excitation mode corresponds to a strong charge transfer excitation. Even though the overlap integral of electron-hole distribution was found to be small in the first excited state, the charge transfer length is comparatively lesser.

The key concepts in selectivity are the Fukui function and the local softness; a highly electrophilic/nucleophilic center is a site presenting a high value of the associated Fukui function. New descriptors such as dual descriptor ( f(r)), a condensed version of f(r) ( s k ) were also calculated for better understanding [45] . Dual descriptor ( f(r)) [45] , is given by: f(r) = f + (r)-f − (r). If f(r) > 0, then the site is favored for a nucleophilic attack, whereas if f(r) < 0, then the site could hardly be susceptible to undertake a nucleophilic attack but it may be favored for an electrophilic attack. s k a condensed version [46] of f(r) multiplied by the molecular softness (S) is given by:

The interpretation is similar to f(r). Table 5 , presents the mulliken atomic charge, Fukui functions, local softness values of all the atoms of the (20) ( continued on next page ) Electrophilicity index ( ω) 3 .1864 Table 4 Overlap integral, charge transfer length, r and excitation energy for different excited states. title molecule. Fig. 9 gives a pictorial representation of fukui functions and dual descriptors, where blue regions correspond to negative regions prone to electrophilic attack and the green regions are positive areas prone to nucleophilic attack. From the table and the figure, it is evident that most of the atomic sites in the molecule are ready to undergo electrophilic attack rather than nucleophilic attack. f(r) value is negative for all the nitrogen and oxygen atoms indicating their favor for an electrophilic attack. All the carbon atoms except C11 and C13 are favorable for a nucleophilic attack.

The antiviral activity of the title compound docked into the active sites of the target proteins was studied from docking parameters. A Dengue RNA viral protein 1R6A [47] and a Hepatitis C viral protein 1HEI [48] were chosen to study the antiviral property of the ligand. The pdb structures of the target proteins are downloaded from RCSB (Research Collaboratory for Structural Bioinformatics) protein data bank ( http://www.rcsb.org/pdb/home/home.do ). Docked conformation which had the lowest binding energy was chosen to study the mode of binding. The molecular docking binding energies (kcal/mol) and inhibition constants (mM) were also obtained and listed in Table 6 ( Table 5 ) H27 was found to have the lowest value of s k ( −0.0 0 012), which indicates that this hydrogen atom acts as a nucleophile while binding to the target protein. Thus the topological analyses of the molecular structure complement the results obtained from the molecular docking studies. Docking results from previous studies [49] shows that the energy value obtained from the docking of Ribavirin with receptor Angiotensin converting enzyme 2 was zero, indicating very low binding affinity towards SARS (Severe Acute Respiratory Syndrome). The antiviral action of ribavirin discussed above showed a better affinity towards viral proteins including dengue virus. Knowledge of Protein-Ligand interaction helps in designing new anti-viral drugs in the future.

In the present work, the experimental and theoretical spectroscopic and topological analyses of Ribavirin using FT-IR, FT-Raman and tools derived from the DFT has been reported. In general, a good agreement within experimental and theoretical normal modes of vibrations was found. Employing the DFT/B3LYP method with 6-311 ++ G(d,p) basis set, the optimized molecular geometry, vibrational frequencies along with infrared intensities and Raman activity of the molecule have been calculated. Frontier Molecular Orbitals analysis reveals the presence of ICT within the molecule, which is further confirmed by the charge transfer interactions due to excitation. The HOMO and LUMO energy values were calculated from which the band gap energy of the title compound was determined to be 6.0146 eV. The electron distribution and the reactive sites on the surface of the title compound were analysed using ESP, ELF and LOL. Fukui functions, local softness for all the atomic sites of the molecule were calculated. In addition, the molecular docking output shows that the title compound acts as a good antiviral agent against the Hepatitis C viral protein, with a low binding energy of −3.53 kcal/mol.

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