DFT Calculations and Molecular Docking Studies on a Chromene Derivative

Chromenes and their derivatives have been considered as an important class of oxygen-containing heterocycles.*ere has been an increasing interest in the study of chromenes due to their biological activity. Herein, the structural, electronic, and vibrational properties of a chromene derivative, entitled 2-amino-5-oxo-4-phenyl-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile and abbreviated as Chrom-D, have been reported. *e FT-IR, UV-vis, and H-NMR and C-NMR chemical shifts’ measurements were recorded. *e molecular geometry and the vibrational frequencies are computed in the frame of density functional theory at the B3LYP/6-311++G(d,p) level of theory. *e noncovalent interactions in the crystal lattice which are responsible to the 3D crystal structure of Chrom-D are investigated based on Hirshfeld surfaces and topological reduced density gradient (RDG) analysis. Molecular electrostatic potential surface, Mulliken charges, and Fukui functions are computed in order to find out the electrophilic and nucleophilic sites. *e electronic properties of the title compound have been studied based on the TD-DFT calculations. Finally, Chrom-D has been evaluated as a multifunctional agent against Alzheimer’s disease (AD).


Introduction
Since its discovery, heterocyclic chemistry was considered as one of the more complex areas of organic chemistry wherein heterocyclic compounds were considered as the largest family of organic compounds. Due to their structural diversity, heterocyclic compounds have proven their efficiency as therapeutic factors [1][2][3]. More specifically, heterocyclic molecules incorporating oxygen atoms are of particular interest. One of the most attractive classes of these materials is the class of chromene compounds, which presents a wide area of expertise for many scientists all over the globe.
Structurally, these compounds contain fused rings of pyran and benzene with different levels of saturation. From a pharmaceutical and medicinal point of view, chromene compounds were and remain considered as a fruitful area of investigation [4][5][6][7][8]. e fundamental aim of the molecular engineering of these materials was to improve their biological, medicinal, and pharmaceutical benefits.
Going deeper insight, relevant bibliographies focused on chromene compounds show that dihydropyrano[c]chromene and its derivatives are of a considerable interest because they possess a broad variety of biological properties, notably antifungal [9], antitumor [10], anti-HIV [11], antimicrobial, and antituberculous drugs [12], as well as muscle relaxants [13]. A series of synthetic dihydropyrano [c] chromene derivatives showed their significant pharmaceutical potential. More specifically, dihydropyrano [3,2-c] chromene and its derivatives are interesting heterocycles used for the treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's, schizophrenia, and myoclonus [14].
Chrom-D, subject of the current report, is one of the most important derivatives of dihydropyrano[c]chromene.
To the best of our knowledge, neither DFT studies nor docking simulation has been reported yet for the Chrom-D compound. Based on these findings, it seems to be crucial to have a whole understanding of the Chrom-D molecule from a potential application point of view. For these reasons, we highlight the molecular structure, spectroscopic and population analysis, noncovalent interactions, and electronic and nonlinear optical properties for Chrom-D. Finally, molecular docking calculation was performed to estimate its antiacetylcholinesterase activity.

Synthesis.
e basic pathway for the preparation of Chrom-D is reported in Figure 1. Further details are given in [15]. e first step of the compound identification was based on the analysis of 1 H-NMR and 13 C-NMR spectra. FT-IR spectroscopy was performed in the second step in order to identify and recognize its characteristic bands. Figure 2(a) illustrates the asymmetric unit of the title compound. Its optimized geometry, with label atoms, is given in Figure 2(b). e structural parameters (bond lengths and angles) are listed in Table 1.

Structural Analysis.
e experimental values are listed for comparison. e low root-mean-square deviation (RMSD) values of bond lengths (0.074Å) and angles (0.9°) show a good agreement between the experimental geometry and the calculated one. e inspection of the structural parameters shows that all calculated C-H and N-H bonds are slightly larger than those obtained by X-ray diffraction.
is deviation may be explained by the scattering factors of hydrogen atoms in the X-ray diffraction. is fact can be interpreted by ignoring the intermolecular and Columbic interactions with the neighboring molecules in the crystal lattice.
As shown in Figure 2, Chrom-D molecule contains four rings: two pyran rings denoted A and B and two phenyl rings named C and D. As discussed before [16], the dihedral angles between the mean plane of ring A and the rings B, C, and D are, respectively, 4.86(4)°, 3.57(5)°, and 84.90(6)°. Also, we can easily notice that ring D is almost perpendicular to the general plane of these rings. e mean bond lengths in the phenyl rings are experimentally 1.382 for C10-C11 and 1.373Å for C26-C27. ese values were computed to be 1.393 and 1.397Å for C10-C11 and C26-C27, respectively. e experimental bond length of the keto groupment C7�O8 is found to be 1.214Å which is comparable to the theoretical value (1.213Å). ese values are typical for double-bond distance. In similar vein, bond lengths of C2-O1, C20-O1, C10-O9, and C7-O9 are found to be 1.369, 1.381, 1.377, and 1.377Å, respectively. eir corresponding calculated values were 1.365, 1.368, 1.368, and 1.383Å. All the geometrical parameters of the studied compound are found to be in conformity with the structural data of similar compounds [17]. e calculation shows that Chrom-D has a high value of dipole moment equal to 11 D. One may conclude that the compound can present significant electronic and nonlinear optical properties. Figure 3 shows the crystal packing projected along the "a"-axis. Obviously, the molecular arrangement of the Chrom-D crystalline packing reveals the presence of the hydrogen bonding N-H· · ·O and C-H· · ·O network linking different molecules to each other.
Different views highlighting the intermolecular interactions are depicted in Figure 4. One may conclude that the crystal packing is really ensured by N-H. . .N, C-H···π, and π ···π interactions. Both hydrogen atoms of the amino group are involved in intermolecular hydrogen bonding sheets.

Hirshfeld Surface Analysis.
Hirshfeld surface analysis is a suitable tool to investigate the intermolecular interactions within the crystal packing [18,19]. e main idea of the Hirshfeld surface is to delineate the space filled by a molecule in a crystal to segment the crystal electron density into molecular fragments.
In this context, at each point of an isosurface, two different types of distances d e and d i are defined, which express the distance from the point to the nearest nucleus external to the surface and the distance to the nearest nucleus internal to the surface, respectively. A three-dimensional molecular surface was created by delineating the normalized contact distance d norm . d norm is defined as where r v dW e and r v dW i are the Van der Waals (VdW) radii of the two atoms external and internal to the Hirshfeld surface. Hirshfeld surfaces of Chrom-D mapped with d norm and the shape index along with the "a"-and "c"-axis are displayed in Figure 5. e intermolecular interactions within the Hirshfeld surface are represented with the color code. e contacts with distances equal to the sum of the VdW radii are shown in white color, and the contacts with distances shorter than and longer than VdW radii are represented as red and blue colors, respectively. e red spots appeared in the d normmapped Hirshfeld surface indicate the N-H ··O and N-H· · ·N intermolecular H-bonds. e shape index is highly sensitive to very subtle changes in the surface shape. It indicates the electron density surface around the molecular interactions. e small range of light colors on the surface symbolizes a weaker and longer interaction other than hydrogen bonds. e presence of red and blue triangles on the surface of the shape index is a characteristic of π. . .π interactions. e 2D fingerprint plots provide all intra-and intermolecular contacts in the form of griddle colored areas in each of d i and d e , as depicted in Figure S1. Herein, the complete Hirshfeld surface indicates that the overall intermolecular interaction is maintained by H. . .H (37%), H-C (18.6%), H-O (18.5%), and H-N (13.6%) contact interactions. All interactions discussed above give rise to the formation of a 3D network of the Chrom-D compound.

RDG Analysis.
e above analysis highlighted the intermolecular contacts giving rise to the stability of the crystalline packing. To deeply investigate the intermolecular interaction within the Chrom-D crystal, we have performed the noncovalent RDG analysis. is method is very popular for the investigation of weak interactions, such as hydrogen bond, VdW, and repulsive steric interactions using a simple color code. Blue, green, and red color codes indicate the presence of hydrogen bonding, VdW, and steric interaction, respectively. Further details for the RDG method are given in [20]. e RDG isosurfaces of the Chrom-D crystal are plotted in Figure 6.
As shown, the big flat isosurfaces, pointed by the red arrow, clearly indicate the π-π stacking interactions. Moreover, all hydrogen bond interactions are appeared as filled-color green surfaces (as indicated by blue arrows). Furthermore, the RDG graph shows the presence of the intramolecular interaction in different positions highlighted with green color. Hence, we can conclude that these interactions can only be regarded like VdW interactions. ese findings lead to charge transfer between pyranbenzene of the first molecule and those of the second entity.
is delocalization is mainly caused by the tautomeric effect within each entity. e red isosurfaces figured within each ring correspond to the steric effect. All these results seem to be in a good matching with the structural data and HS analysis discussed previously.

Population Analysis.
e molecular electrostatic potential (MEP) surface, Mulliken charges, and Fukui functions are calculated for the titled compound. MEP surface has been generated at the same level of theory and displayed in Figure 7.
is technique is a visual tool to envisage the electrophilic and nucleophilic behavior of the studied compound [21][22][23][24]. As shown in Figure 7, the negative regions, highlighted by red color, are laid around C�O of ring B and C≡N of ring A which may be explained by the tautomeric effects as well as their implication on the H-bonding network. e positive region, highlighted by darkest blue color, appeared around the NH 2 group of ring A which supports the formation of strong hydrogen bonding. Obviously, the nucleophilic and the electrophilic behaviors around the C�O and C≡N groups and NH 2 group, respectively, support the presence of intermolecular interactions between different molecules forming the crystal packing.
e Mulliken charge distribution of Chrom-D has been carried out, and the values are given in Table S1  highest negative charges were occupied by oxygen atom O8 and nitrogen atom N25. It confirms the presence of a system of N-H···O, C-H···O, and N-H···N H-bonding.
ese parameters examine the tendency of a molecule to lose or gain an electron, thus predicting which atom in the molecule would be more prone to a nucleophilic or electrophilic attack.
e Fukui function f j + , referring to a gain of an electron, is commonly called the index of nucleophilic attack. Despite, the loss of an electron is designed by the Fukui function f j − which is also termed the index of electrophilic attack. e condensed atomic Fukui functions for electrophilic f j − , nucleophilic f j + , and radical f j°a ttacks on the j th atom site are defined as where q j is the atomic charge (Mulliken, Hirshfeld, or NBO) at the j th atomic site and (N), (N − 1), and (N + 1) are the total electrons present in the neutral, cation, and anion state of the studied molecule, respectively. e condensed dual descriptor Δ f(r) is defined as e condensed Fukui functions and dual descriptor, calculated based on the NBO charge distribution, are listed in Table S2.   Negative values of Fukui functions indicate that an addition of one electron to the molecule reduces its electron density. Instead, excluding an electron leads to an increase in the electron density. Negative values of Δ f(r) indicate that the corresponding atoms are prone to the electrophilic attack, whereas positive values reveal that the corresponding atoms are prone to the nucleophilic attack. In the case of our investigated compound, the order of the reactivity was classified as N21 > O8 > N25 > C3 > O1 > O9 for "nucleophilic atoms" and as C7 > C2 > H22 > H23 > C24 for electrophilic atoms.

Vibrational Analysis.
e infrared spectrum of the Chrom-D compound is recorded in the range between 400 and 4000 cm −1 and plotted with the calculated one in Figure 8. e observed and calculated wavenumbers as well as the probable assignments of fundamental vibrational modes are given in Table 2.
Applying a scale factor [30,31] is a moderator to overcome the misleading between experimental and computed values. e title molecule is formed by 36 atoms which undergo with 102 normal vibrational modes. e optimized structure deals with the C 1 point group symmetry. eoretical and experimental IR spectra analysis of Chrom-D has been made based on the main characteristic of N-H, C≡N, C-H, and C�O vibrations. e stretching modes of the NH 2 amino group are generally appeared in the region of 3500-3380 and 3400-3250 cm −1 , for symmetric and asymmetric vibrations, respectively [32]. In the current work, the asymmetric and symmetric NH 2 vibrations are observed at 3377 and 3305 cm −1 , respectively. eir corresponding calculated wavenumbers are 3533 and 3427 cm −1 . is vibration mode is considered as a pure mode regarding to its TED contribution (99%). e broadening of the bands reveals a strong hydrogen-bonding interaction between the adjacent molecules through their N-H groups. e literature reveals that the stretching vibrations of the triply bonded groups were expected to be in the range of 2500-2000 cm −1 [33]. Herein, the C≡N stretching vibration is observed at 2199 cm −1 in the infrared spectrum. Its calculated frequency is found to be at 2180 cm −1 . is vibration may be affected by the hydrogen bonding between C≡N and NH 2 in the crystal lattice.
Generally, the C-H stretching vibrations are found between 3100 and 3000 cm −1 . In our case, C-H stretching vibrations are observed between 3093 and 3000 cm −1 . For the C�O stretching, a broad band located at 1660 cm −1 in the theoretical spectrum can be accredited to this stretching. Experimentally, this band was observed at 1715 cm −1 . Besides, another strong band appeared, theoretically, at 1656 cm −1 (64%) which may be assigned to C�C stretching vibrations. All these results with the appropriate TED percentage and assignments are given in Table 2. e correlation between the scaled and experimental frequencies is plotted in Figure 9. From the graph, a linearity was found between the scaled and the observed frequencies.
e correlation coefficient (R 2 ) is found to be 0.99925. us, it may be concluded that the calculated frequencies are consistent with the experimental ones.

NMR Spectral Analysis.
NMR spectroscopy is one of the most important techniques used for the structural analysis of organic molecules [34]. 1 H-NMR spectrum gives information about the number of different protons and the nature of their chemical environment. e 13 C-NMR spectrum provides the structural information about carbon atoms. Starting from the optimized structure, 1 H-NMR and 13 C-NMR were calculated, in the gas phase, using the gaugeincluding atomic orbitals (GIAO). e predicted 1 H-NMR and 13 C-NMR isotropic chemical shifts with respect to the TMS B3LYP/6-311+G(2d, p) GIAO reference are listed and compared with the experimental data in Table 3.
Experimental 1 H-NMR and 13 C-NMR spectra recorded in DMSO-d 6 are illustrated in Figure 10.
Accordingly, all 1 H-NMR chemical shifts are localized in the range between 7.914 and 7.249 ppm, except H4 (H5 in Table 3), wherein its chemical shift was 4.449 ppm. ese results are similar to those obtained by Sharma et al. [16].     [35,36]. Concerning the 13 C-NMR chemical shifts, results show that B3LYP/6-311++G(d,p) has slightly overestimated the experimental values. Herein, experimentally, the 13 C-NMR chemical shifts are found approximately in the range of 37-160 ppm, whereas theoretically, the values are varied closely between 43 and 163 ppm.

Electronic
Properties. TD-DFT calculations have been performed at the same level of theory to predict the absorption spectrum, excitation energies, absorption wavelengths, and oscillator strengths along with the electronic transitions and their contributions. e calculations were made in DMSO solvent within the IEFPCM solvation model. Experimental and calculated UV-vis spectra are depicted in Figure 11. Absorption wavelengths (λ), oscillator strengths (f ), and excitation energies (E) along with major contributions of the transitions are listed in Table 4.
As we can notice, the absorption takes place approximately between 200 and 400 nm. ree intense electronic transitions are predicted closely at 224, 246, and 306 nm. As  shown in Table 4, the highest oscillator strength is calculated at 307 nm (f � 0.301). Furthermore, the investigated molecule has benefits of remarkable transparency and low absorbance as shown experimentally.
is behavior is considered as a good indication for the NLO applications. HOMO and LUMO frontier orbitals are extracted and plotted in Figure 12.
Obviously, the HOMO orbitals, lying at −6.49 eV, are localized mainly on the amino, carbonitrile, and phenyl groups. Despite, the LUMO orbitals, lying at −2.36 eV, cover the whole molecule except the phenyl group. As discussed in several previous works, the HOMO-LUMO gap energy characterizes the chemical reactivity and kinetic stability of a studied compound [37][38][39][40]. us, a molecule with small gap energy is more polarizable, generally, shows a high chemical reactivity and low kinetic stability, and is qualified as a soft molecule. Here, the HOMO-LUMO gap energy is calculated to be 4.13 eV. is relatively low value makes the molecule more reactive. Based on the HOMO and LUMO energy values given in Table 5, the global chemical reactivity descriptors such as hardness (η), chemical potential (µ), softness (S), electronegativity (χ), and electrophilicity index (ω) have been calculated using the following equations: η � (IP − EA)/2, µ � −(IP + EA)/2, S � 1/2η, χ � (IP + EA)/2, and ω � μ 2 /2η, where IP and EA are the ionization potential and electron affinity, respectively. e electron affinity is the amount of energy spent to the neutral molecule to gain precisely one electron from a donor. IP and EA can be expressed through HOMO and LUMO energies as IP � −E HOMO and EA � −E LUMO . Accordingly, the ionization potential and the electron affinity of the title compound are 6.49 and 2.36 eV, respectively. e calculated values of the global hardness, global softness, chemical potential, and global electrophilicity index are 2.06, 0.24, −4.43, and 4.75 eV, respectively. Its low value of the chemical potential and high value of the global electrophilicity index point to a considerable electrophilic character of the molecule. In addition, the dipole moment calculated in DMSO solvent is found to be 11 D. is value supports the presence of several intermolecular interactions and confirms the tautomeric effect within the crystal lattice.

Nonlinear Optical Properties.
In the current research field, NLO is the most useful concept to evaluate optoelectronic properties of a molecular system [41]. In order to get insight about the nonlinear optical properties of the studied compound, the dipole moment, polarizabilities, and first-order hyperpolarizabilities have been calculated in the gas phase and in DMSO solvent. e total dipole moment and first-order hyperpolarizability of Chrom-D are found to be 11 D and 5.02 × 10 −30 esu, respectively. Based on these findings, Chrom-D has a total dipole moment of 8 times greater than that of urea (5.5 times in the gas phase). Besides, the firstorder hyperpolarizability is almost 13 times greater than that of urea (μ and β of urea are 1.3732 D and 0.3728 × 10 −30 esu). e high value of first-order hyperpolarizability explains the intramolecular charge transfer within the molecule. erefore, the highest value of the β YYY -component of the first-order hyperpolarizability points to a charge delocalization along the "YYY" direction. is charge delocalization has been proved by the low gap energy (4.13 eV). e above results allow us to conclude that Chrom-D is an outstanding material for NLO applications. 10 Journal of Chemistry 2.10. Molecular Docking. Molecular docking simulation aims to predict the best binding configuration of a ligand to a macromolecular partner. It generates a number of possible conformations/orientations, i.e., poses, of the ligand within the protein binding site. e best pose ligands were selected on the basis of their best conformation that allows the lowest free binding energy [42]. iGEMDOCK explores an interactive interface for preparing the binding site and ligand docking status, postdocking analysis, monitoring the progress, ranking, and visualization of the screened compounds by combining the pharmacologic interactions and the energy-based scoring function [43,44]. e molecular docking has been performed to study the inhibitor activity of Chrom-D as a ligand against AChE enzymes. e inhibition of AChE has appeared as one of the most promising strategies for the AD treatment and plays a crucial role in the acetylcholine-mediated neurotransmission [45][46][47][48]. e structures of AChE enzymes (1B41, 1EVE, and 1BDT) are taken from the Protein Data Bank. en, eventual cocrystallized ligands and water molecules have been removed. e best-docked poses having the lowest energy from a total of 10 poses for each enzyme are retained. Intermolecular      Journal of Chemistry 13 interactions between amino acids of the binding site and Chrom-D, for the best-docked state, were visualized using Discovery Studio 2017 R2 Client software. e best poses of the ligand Chrom-D in the AChE enzymes along with ligand/enzyme interactions in 2D diagrams are plotted in Figure 13. e docking energies are listed in Table 6. e ligand-enzyme interactions are mainly ensured by VdW and hydrogen-bonding types. Referring to the   e calculated values of the interaction between the residue and the Chrom-D ligand are given in Table 7.
ese results show that most of interactions are associated to TRP86 and for 1B41 and 1BDT with −19.2 and −34.0 kcal mol −1 , respectively, whereas the highest value was calculated for the interaction between PHE330 and 1EVE. e corresponding value is found to be −13.8 kcal mol −1 . ese results point to a good inhibitor activity of our studied compound.

Conclusion
In this work, the structure of Chrom-D has been investigated using several experimental techniques, X-ray diffraction reported previously by Sharma et al., IR, NMR, and UV spectroscopy. Its molecular geometry has been optimized with DFT calculation. All intermolecular interactions taken place between different components of the molecule have been, deeply, discussed in terms of Hirshfeld surfaces and RDG to confirm the structural data. ese techniques prove that the crystal structure is mainly stabilized through the hydrogen-bonding interactions between carbonyl of pyran rings and the amino groups of its adjacent neighbors. In the second part of this study, we identified the nucleophilic and electrophilic attacks through the calculation of MEP, Mulliken charge distribution, and Fukui functions. en, the vibrational modes have been calculated and assigned to the experimental frequencies. Also, HOMO-LUMO gap energy calculated in the frame of the TD-DFT method was found to be 4.13 eV, which explains the charge transfer within the molecule. is relatively low HOMO-LUMO gap and the high value of the dipole moment (11 D in DMSO solvent) confirm the reactivity of the Chrom-D molecule. Besides, the calculated polarizability and first-order hyperpolarizability for the isolated molecule support the idea that the title compound is an excellent candidate for the fabrication of nonlinear optical (NLO) devices. Finally, the molecular docking simulation showed that Chrom-D has the potential to inhibit acetylcholinesterase.
3.1. Experimental Section. 1 H-NMR (300 MHz) and 13 C-NMR (75 MHz) spectra were recorded in deuterated CDCl 3 and DMSO-d 6 using Bruker AC-300. All chemical shifts indexed as δ values (ppm) and coupling constants (J) were expressed in Hz. At ambient temperature, the FT-IR spectrum was recorded as a KBr pellet using the Jasco 4100 FT-IR spectrophotometer.
e UV-vis spectrum of our investigated compound was performed at 25°C in DMSO solvent using concentration equal to 5.10 −5 M.

Computational Details.
Starting from the X-ray structure determined by Sharma et al. [16], the geometry of Chrom-D is optimized in the ground state at the B3LYP/6-311++G(d,p) level of theory using Gaussian 09 program package [49]. e calculation is performed in DMSO solvent associated to the IEFPCM solvation model and without any constraint on the geometry. e results were visualized by using GaussView program [50]. e convergence to a global minimum of the optimized geometry is confirmed by the absence of imaginary frequency. e vibrational assignments have been performed on the basis of total energy distribution (TED) using VEDA4 program [51]. e Hirshfeld surfaces and the fingerprint 2D plots are generated by using CrystalExplorer 3.1 package [18,19]. e RDG function is plotted by means of Multiwfn [52] and VMD [53] programs. e UV-vis spectrum is calculated in the frame of the TD-DFT method at the same level of theory. e contributions of electronic transitions are identified with GaussSum program [54]. e docking simulations of Chrom-D as an acetylcholinesterase inhibitor against AD were made using two protocols. For the first one, the molecular docking between Chrom-D as a ligand and the AChE enzymes was carried out using iGEMDOCK software [43,44]. In the second one, we have used AutoDock Vina program [55].
e Discovery Studio 2017 R2 Client program was used for the preparation of enzymes and the visual representation of ligand-enzyme interactions in the best poses.

Data Availability
e data used to support the findings of this study are available from the corresponding author upon request. Disclosure e funders had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.