Theoretical Investigation of Two Antiemetic Drugs at DFT Level

Corresponding Author: Khalil Errahmane Kanouni Laboratoire Préparation, Modification et Application des Matériaux Polymériques Multiphasiques, LMPMP, Department of Processes Engineering, Ferhat Abbas University, Sétif-1, Algeria Email: khalilkanouni@hotmail.com Abstract: The geometries and the bonding properties have been predicted for two antiemetic drugs using Density Functional Theory method (DFT). Mulliken population and frontier molecular orbital analysis with the determination of the physicochemical properties was performed using the Amsterdam Density Functional package (ADF). To calculate the exchangecorrelation energy, the Generalized Gradient Approximation of BeckePerdew (GGA-BP) was used. The most important finding is the still acceptable reliability of this method in predicting the physicochemical properties for the two organic drugs used in this study. The theoretical results obtained from the ADF software are compared with experimental ones obtained from literature. It was showed that the calculated properties were satisfactorily close to the experimental ones.


Introduction
Nowadays, the development of new drugs is becoming easier (Nicola et al., 2019) to be performed by pharmaco-chemists (Vasava et al., 2019) with simple commonly used computers and having basic notions of molecular and quantum mechanics (Henderson, 2018).
Molecular Modeling (MM) (Pal, 2020a) is a set of theoretical physical methods and computer techniques (Uto et al., 2018) that attempt to virtually mimic the behavior of molecules (Schommers, 2019). MM is the investigation of the molecular structures (Vokáčová and Pluhařová, 2019) and physical properties, using computer-based computational chemistry and graphical visualization techniques (Miao et al., 2019) to provide a plausible 3D representation under defined circumstances. MM involves the use of theoretical calculation methods (molecular mechanics (Ladefoged et al., 2019), molecular dynamics, ab initio or semi-empirical quantum mechanics, etc.) to determine the graphical representation of the geometry or the molecule configurations and to evaluate its physicochemical properties (Kwon and Moon, 2019). MM associated with an infographic representation of the stereochemistry allows to interpret the physicochemical property (Lecerf et al., 2019), to suggest new experiments (Baake et al., 2019) and to analyze results in a more critical way than the classically used experiments (Islam et al., 2019). By the way, the theoretical approaches and experimental studies are complementary (Ahmed et al., 2019).
Recently, MM has gained considerable momentum in many areas of application (Madikizela et al., 2018), namely pharmaceutical industry, biology and condensed matter (Olson, 2018). This is the set of techniques for studying and treating chemical problems on a computer without the need to go into the manipulation room to mount experiments (Jingna et al., 2019). Theoretical calculations are increasingly used in interpretations of experimental data which for some systems may be very complicated or even impossible to interpret experimentally (Piñeiro et al., 2019). They are used to predict reaction processes (Gao and Jiang, 2019) and behavior of system under very hard experimental conditions such as extreme pressure or temperature.
The number of articles published in this thematic is very reduced because of the method novelty (molecular modelling) and those published in literature are limited only in experimental studies: MADEJ and SIMPSON studied the efficacy of many antiemetic drugs and they concluded that metoclopramide significantly reduced the incidence of nausea and vomiting; domperidone decreased the incidence of postoperative nausea alone. The occurrence of extrapyramidal reactions was similar for the two drugs (Madej and Simpson, 1986). Roila et al. (1987) have carried out a study on sixtytwo patients treated for the first time with intravenous Cyclophosphamide-Methotrexate-5FU (CMF) and they confirmed that domperidone is clearly less efficacious than metoclopramide and probably has no place in the prevention of emesis in (CMF) treated cancer patients and they suggest that metoclopramide is more efficacious in the prevention of nausea and vomiting in CMF treated patients.
The physicochemical properties of these two molecules were determined after the geometry optimization (Dinc et al., 2019). Calculations were made with the ADF 2013 program.

Results and Discussion
Molecular geometries were Optimized using the GGA-BP exchange-correlation functional (Bezzerrouk et al., 2015) in the ADF program. The TZVP basis set (Myllys et al., 2016) and tight SCF convergence criteria (Sun et al., 2017) were used for calculations.
In this study the use of delocalized coordinates significantly reduces the number of geometry optimization iterations needed to optimize the molecules compared to the use of traditional Cartesian coordinates. Some of the geometries optimized were also subjected to full frequency analyses to verify the nature of the stationary points. Equilibrium geometries were characterized by the absence of imaginary frequencies.
The domperidone molecule is given in Fig. 1, where the metoclopramide is shown in Fig. 2.

Mulliken Population and Frontier Molecular Orbital Analysis
Mulliken charges are derived from the Mulliken population analysis (Yadav et al., 2020) and allow to estimate the partial atomic charges where the numerical chemistry methods are used in the calculations, as well as those based on the linear combination of atomic orbitals (Pemmaraju et al., 2018).  Generally, the tendency to donate electrons to an appropriate acceptor molecule is indicated by a high value of the energy ξHOMO (Lin and Wang, 2018) and the high electron accepting ability of the molecule is indicated by a low value of the energy ξLUMO (Xie et al., 2019). The energies of the molecular orbitals ξHOMO and ξLUMO are used to calculate the electronic chemical potential μ (Barhoumi et al., 2019) and the global hardness ƞ (Arab et al., 2016) as follows: Physically, µ is able to describe the escaping tendency of electrons from an equilibrium system and ƞ is related to the resistance towards the deformation or the polarization of the electron cloud of the molecules (Vittone et al., 2019).
The following relation express the electrophilicity index ω, which is calculated using the two previous parameters: μ and ƞ: The electrophilicity index expresses the ability of an electrophile to acquire an additional electronic charge (Rezende and Aracena, 2012). The notion of dipole moment in physics and chemistry is expressed by the existence of many electrostatic dipoles . It is a heteroclite distribution of electrical charges such that the barycenter of the positive charges does not coincide with that of the negative charges (Inamdar et al., 2018). The simplest dipole is therefore a pair of two charges, of opposite signs, separated by a non-zero distance (Pal, 2020b).
According to Table 1, The chemical potential of the two molecules are very close indicating that the two molecules have an escaping tendency of electrons from an equilibrium system very similar (Slightly higher for domperidone). The two molecules were found to be very stable with ƞ equals 0.0656 and 0.0513 Ha, respectively. It is obvious that the domperidone has a more hardness than metoclopramide (Adly et al., 2019).
The electrophilicity index (ω) of the metoclopramide is higher than that of domperidone indicating that metoclopramide is abler to accept electrons (Wei et al., 2019). The dipole moment of domperidone, D = 1.9099 Debye, is very close to that of water Dwater = 1,9 Debye but for metoclopramide, D = 4.8654 Debye. This difference in the dipole moments between these two molecules is due to the difference in the distribution of atoms (Morosanu et al., 2019) (especially the most electronegative) in the structures of their Molecules. The high value of the dipole moment of metoclopramide may increase its interaction with polar molecules like water which explains its higher solubility (Chung and Kesisoglou, 2018).
According to Table 2 giving Mulliken charges for the domperidone molecule, O(10) and O(28) have the lowest negative charge, it is noticeable that the O(28) oxygen atom HOMO electronic cloud is higher than that observed for O(10) showing that O(28) is the more able atom for the electrophilic attack. The highest positive charge was found for C(9) which is favorable for the nucleophilic attack. The HOMOs and LUMOs (Fig. 3) are mainly located over the two oxobenzimidazolyl. In this molecule, the energy gap between HOMO and LUMO/HOMO-1 and LUMO+1 is 0.1312ev/0.147ev, respectively.  According to the Table 3, the Mulliken charges for the metoclopramide molecule indicated that the oxygen atom O(6) has the lowest negative charge (favorable to the electrophilic attack) (Haseena et al., 2019) and the carbon atom C(11) has the highest positive charge (favorable to the nucleophilic attack) (Yan et al., 2019). The HOMOs and LUMOs (Fig. 4) are mainly located over the two methoxybenzamide except the HOMO that was located over the triethylamine. In this molecule, the energy gap between HOMO and LUMO/HOMO-1 and LUMO+1 is 0.1026ev/0.1472ev, respectively. The calculated energy gaps for the two molecules were found quite similar for HOMO-1: LUMO+1, but the HOMO: LUMO energy gap for domperidone was higher. This means that metoclopramide is more reactive than domperidone (Toppare et al., 1994). The location of HOMOs and LUMOs, showed the presence of benzyl and amine for the two molecules. This will indicate that the two molecules have a quite similar affinity to attack the active site (Chen and Wang, 2019). Regarding the electrophilicity (Table 1), it is noticed that close values were calculated for domperidone and metoclopramide. It is concluded that both molecules have the same electrophilic/nucleophilic character with respect to the receptor site (Ma and Cahard, 2007). This finding, allowed us to conclude that these two molecules attack the same receptor site (Rossi et al., 2010) since they already have the same therapeutic activity. That said, the two antiemetics (domperidone and metoclopramide) have the same effect in the human organism (Baum et al., 1984).

Physicochemical Properties
To calculate physicochemical properties, the COnductor-like Screening MOdel for Realistic Solvents (COSMO-RS) (Abranches et al., 2019) was used.
The computed physicochemical properties given in Tables 4 and 5 are found to be close to the experimental values. The vapor pressure given for the two molecules show the low volatility of the domperidone and metoclopramide.
The computed boiling point were found to be very high 629.9 and 415.38°C for domperidone and metoclopramide respectively (Ohe, 2019). The melting point was found 240.09 and 144.21°C for domperidone and metoclopramide respectively. It is remarkable that the temperature ranges in which the two drugs are in the liquid phase is very large. it is also noted that the melting and boiling temperatures of the metoclopramide are the lowest.
Log P characterize the hydrophilic or lipophilic character of a molecule (Chmiel et al., 2019) and calculated by the logarithm of the partition coefficient between octanol and water. It is used to evaluate the bioavailability of a molecule: Log P< 0, the molecule is said hydrophilic; Log P >5, the molecule is lipophilic; A good balance is needed between the hydrophilic and hydrophobic character for an optimal biological activity 0<Log P<5 (de Oliveira et al., 2019). A molecule with an optimal biological activity is sufficiently hydrophilic to be soluble in aqueous media (blood, cytoplasm...) and in the same time it must have a hydrophobic character to pass through the membranes (Pieńko et al., 2016). It should be noted that the partition coefficients of the two molecules have optimal biological activity (Sagandykova et al., 2018) with 3.808 and 2.592 for domperidone and metoclopramide respectively.
The pKa for the two molecules is greater than 7 indicating a basic character for both molecules. That said, the basicity of metoclopramide is higher (Tang et al., 2014).
The solubility of metoclopramide is much higher than that of domperidone, which means its ease blood transport (Arnau and Vallano, 1993).

Conclusion
This novel method (theoretical study) was set out to determine some physicochemical properties like partition coefficient, solubility, pKa, etc. The experimental physicochemical properties of domperidone and metoclopramide are calculated with confidence using the GGA-BP exchange-correlation functional and the TZVP basis sets with tight SCF convergence criteria for calculations. The geometry optimization, population analysis and Mulliken charges were calculated and analyzed using the same method with the same parametrizations. This results obtained theoretically were compared with the experimental ones. The application of the theoretical methods such as molecular dynamics, allowed the determination of physicochemical properties of the two antiemetic drugs. The calculated properties values were quite close to the experimental ones especially the boiling point, the melting point and the solubility. This further study reinforces the choice of the molecular modeling as an indispensable tool in the development of drugs and pharmaceutical theoretical chemistry and leading to reduce the number of laboratories experiments.