key: cord-0741867-dypbci7j authors: Noureddine, Olfa; Issaoui, Noureddine; Al-Dossary, Omar title: DFT and Molecular Docking Study of Chloroquine Derivatives as Antiviral to Coronavirus COVID-19 date: 2020-11-25 journal: J King Saud Univ Sci DOI: 10.1016/j.jksus.2020.101248 sha: 3c2a00f3aa67ec5ce6dd726f24f5679836621c83 doc_id: 741867 cord_uid: dypbci7j The recently emerged COVID-19 virus caused hundreds of thousands of deaths and instigated a widespread fear, threatening the world’s most advanced health security. In 2020, chloroquine derivatives are among the drugs tested against the coronavirus pandemic and showed an apparent efficacy. In the present work, the chloroquine and the chloroquine phosphate molecules have been proposed as potential antiviral for the treatment of COVID-19 diseases combining DFT and molecular docking calculations. Molecular geometries, electronic properties and molecular electrostatic potential were investigated using density functional theory (DFT) at the B3LYP/6-31G* method. As results, we found a good agreement between the theoretical and the experimental geometrical parameters (bond lengths and bond angles). The frontier orbitals analysis has been calculated at the same level of theory to determine the charge transfer within the molecule. In order to perform a better description of the FMOs, the density of states was determined. The molecular electrostatic potential maps were calculated to provide information on the chemical reactivity of molecule and also to describe the intermolecular interactions. All these studies help us a lot in determining the reactivity of the mentioned compounds. Finally, docking calculations were carried out to determine the pharmaceutical activities of the chloroquine derivatives against coronavirus diseases. The choice of these ligands was based on their antiviral activities. In late December 2019, the coronavirus [1] was first reported in humans in Wuhan, China, and appeared as a rapidly spreading pandemic [2, 3] . About 46 million people worldwide have been infected as of 1, November 2020, and over 1 197 000 have died. It is worthy to mention that this pandemic has the same symptoms as a flue. Fatigue, fever, headache, runny nose and dry cough are the principal clinical symptoms of COVID-19. Thus far, there is no effective antiviral medication or vaccine against COVID-19 virus has been developed. Where the World Health Organization announced it as one of the most dangerous health catastrophes in human history [4] since this virus is accelerating very quickly more than predicted by experts [5] . Therefore, searching for effective antiviral agents to battle against this virus is urgently needed. In this context, our investigations are destined for the development of therapeutic agents for COVID-19 diseases. Many scientists are working on the designing of efficacious antiviral agents with few aspect effects. Where recent research informed an inhibitor effect of the chloroquine and its derivatives on the growth of coronavirus [6] [7] [8] . Clinical trials have been done on Chinese patients COVID- 19 ; have shown that the chloroquine has a great effect in terms of clinical results and viral clearance, in comparison to the control groups [9] . They have been proposed as a potential antiviral for the treatment of COVID-19 diseases based on their antiviral activities [10, 11] . In this study, we evaluated the antiviral efficiency of two approved drugs which are chloroquine and chloroquine phosphate against the COVID-19 using molecular docking calculations. Docking is a technique of designing drug molecules via computer-aided by simulating the geometric of these molecules and their intermolecular forces [12, 13] . From this calculation, we can predict the different interactions between medications and targets which have an important role in the investigation of the mechanism of the effects of drugs. In this context, many nowadays papers is dedicated to searching in drug design using molecular docking studies [14] [15] [16] [17] . In the same frame, we can cite our previous paper [18] in which we used molecular docking analysis in the determination of the biological activity of the Niclosamide compound. As a result, the niclosamide is found to be a good inhibitor of the COVID-19 virus and can, therefore, be effective in controlling this disease. The main contribution of this paper is to identify the potency of inhibition of chloroquine derivatives against COVID-19 virus by using a molecular docking study. To this end, we first determine the optimized structures of chloroquine and chloroquine phosphate molecules by using the density functional theory (DFT) at B3LYP/6-31G* level of theory. Utilizing optimized structures is more exact in docking calculations, which makes the program more trustworthy to be employed in structure-based drug design. Subsequently, their reactivities were foreseen at the same level of theory by using the frontier orbital studies [19, 20] . From this analysis, we can found the most reactive antiviral ligand. Moreover, molecular electrostatic potentials surfaces were carried out to investigate which are the most reactive nucleophilic and electrophilic regions of a molecule against reactive biological potentials. Docking calculations were performed using four structures of COVID-19 (PDB codes: 6M03, 5R7Y, 5R81 and 6LU7) [21]. Basing on the binding affinities and the different interactions that exist between amino acid residues and ligands, molecular docking results were discussed. Thereafter, Rapid-Screening docking was carried out using iGEMDOCK program [31] . It is a Drug Design System for docking calculations and screening by BioXGEM labs. All the trials were docked with a population size set to 800, with 80 generations and 10 solutions. Optimized structures and numbering of atoms of chloroquine and chloroquine phosphate molecules are shown graphically in Figs. 1 and 2, obtained at B3LYP/6-31G* method. Table 1 illustrates their geometrical parameters such as the calculated total energies, the dipole moments, the RMS and the maximum Cartesian force. The global minimum energies are found to be -1326.0352 a.u (≈ -36083 eV) and -2614.3242 a.u (≈ -71139) for chloroquine and chloroquine phosphate, respectively. The RMS Cartesian force values are equal to 2.412 .10 -6 , 0.04067 in chloroquine and chloroquine phosphate. Their maximum Cartesian forces are found to be 8.593 .10 -6 and 0.1449. The dipole moment of a molecule is given in the form of a three-dimensional vector and which reflects the molecular charge distribution. Hence, it can be employed as a descriptor to describe the charge movement throughout the molecule. As a result of DFT/B3LYP/6-31G* calculations, the highest dipole moment was observed for the chloroquine phosphate (~ 24.49 Debye) whereas the smallest one was observed for the chloroquine (~ 6.05 Debye). Of course, the adding of other atoms in the geometry of the chloroquine has an influence on their stability. We can notice that the chloroquine compound becomes more stable when adding the phosphate groups since the global minimum energy decreases. Also, the strong increase in the dipole moment value shows that the chloroquine is harder before adding the phosphate groups. Moreover, it promotes the formation of hydrogen bonds. The optimized geometrical parameters of chloroquine derivatives have been determined by the above method and they are given in Tables [33] . We find that the RMSD value is equal to 0.065 Å for the bond distances and 3.382° for the bond angles. Results reveal that the carbon-carbon bond distances are found in the range 1.374-1.546 Å for C 20 -C 22 and C 5 -C 7 , respectively for the chloroquine. In the benzene ring (I), the carbon-carbon bond lengths C 13 -C 17 , C 13 -C 18 , C 17 -C 20 , C 18 -C 21 , C 20 -C 22 Table 4 , where orbital energies, energy band gap and reactivity descriptors (like electron affinity, chemical softness, ionization potential, chemical softness….) are reported. The gap between two energetic states describes the molecular chemical reactivity. The Using the energies of FMOs, we calculated the reactivity descriptors of chloroquine and chloroquine phosphate molecules. A= −E LUMO : represent the electron affinity; I = −E HOMO represent the ionization potential and μ= 1/2(I+A) is the electronic chemical potential. The chemical hardness (η) is found to be 2.239 and 2.629 eV for chloroquine and chloroquine phosphate, respectively. The chemical softness () has been computed and found to be 1.1195 and 1.3145 eV -1 . Moreover, the electrophilicity index () is about 2.512 eV for chlroquine and 2.912 eV for chloroquine phosphate. Based on the value found of the electrophilicity index, we can conclude that the chloroquine phosphate is a good electrophile better than chloroquine. Therefore, it is able to accept an electron doublet in order to form bonds with another reagent which is necessarily a nucleophile. Electronegativity is also determined (χ= (I+A)/2) and it is found to be χ chloroquine =3.3545 eV and χ chloroquine phosphate =3.9135 eV. The molecular electrostatic potential (MEP) is a well-established tool for the study of Molecular docking studies of chloroquine and chloroquine phosphate ligands were carried out with four structures of COVID-19 protein (PDB ID: 6M03, 5R7Y, 5R81 and 6LU7). The two ligands were tested for drug-likeliness properties. Calculations were performed using the iGEMDOCK program through the generic evolutionary method (GA) and an empirical scoring function. Both ligands and target proteins structures were adapted with Discover Studio Visualizer software. All crystallographic water molecules were removed. Our goal is to determine the modes of interaction of protein-ligand complexes while looking for favorable orientations for the binding of a ligand to a receptor [40] [41] [42] [43] [44] . In our case, the receptor represents the COVID-19 protein which has one or more specific active sites, more or less accessible. At each step, the interactions are affected and the best pose of the ligands is determined. 10 poses have been obtained; we have chosen the best pose with the lowest energy. These best poses were selected for investigating the different types of interactions that introduce a biological signal. The examination of Table 5 revealed that the chloroquine ligand presented the highest total energy score with the target protein 6M03 which is equal to -81.866 kcal/mol. Note that the total energy is the sum of the three energies interactions: VDW, hydrogen band and electronic. Van der Waals interaction is a potential energy of attraction between two In order to upgrade the recognition of the interactions existing between receptor and ligand, the affinities of these complexes were calculated by using AutoDockTools (ADT) [45] . These affinities describe the strength of a non-covalent interaction between the ligand and its target which binding to a site on its surface. It is premised on the numeral and the nature of the physicochemical interactions. As illustrated in Table 5 , the affinities values (in ultimate value) of chloroquine are found to be in the order of 6.7>6.6>6.1 kcal/mol for (6M03 and 5R81), 5R7Y and 6LU7, respectively. According to the energetic related results of the docking calculations and the corresponding docking positions, the chloroquine phosphate has better binding interaction with 5R7Y protein (as seen in table 5 and fig. 8 ). This protein strongly interacts with the The results obtained show that the chloroquine penetrates well into the active areas of the protein. Therefore, it can be considered to be a potent inhibitor against COVID-19 diseases. But the chloroquine phosphate molecule showed a better activity rather than chloroquine since it interacts stronger with the receptor. This can be justified by the effect of the addition of the phosphate groups. Of course, each compound has its own characteristics that distinguish it from the rest. The chloroquine phosphate is initially made up of chloroquine. Evidently, the adding of other atoms in the geometry of the chloroquine has an influence on their stability. The chloroquine compound becomes more stable when adding the phosphate groups since the global minimum energy decreases. Moreover, the smallest dipole moment was obtained for the chloroquine whereas the highest one was obtained for the chloroquine phosphate. This increase shows that the chloroquine is harder before adding the phosphate groups and also it promotes the formation of hydrogen bonds. We also find that by adding phosphate group the gap energy decreases, which involves a high reactivity for the chloroquine phosphate. This decrease in gap energy makes the flow of electrons easier, so the molecule becomes soft and more reactive. Given their high efficiency in the treatment against COVID-19 pandemic, chloroquine derivatives have been studied combining DFT method and molecular docking calculations. The optimized molecular structures of chloroquine and chloroquine phosphate have been carried out using DFT/B3LYP/6-31G* method and their geometrical parameters were also determined. The comparison of the observed and calculated results showed a good agreement. Molecular properties such as frontiers orbitals, gap energies and reactivity descriptors have also been discussed. Results reveal that the addition of the sulfate group resulted in a decrease in the gap energy, which involves an expected high reactivity for the chloroquine phosphate. This decrease in gap energy makes the flow of electrons easier, so the molecule becomes soft and more reactive. The density of states (DOS) was determined and it allowed bettering describing the border orbitals. Thereafter, the calculated MEP maps show the positive potential sites are favorable for nucleophilic attack, whereas the negative potential sites are favorable for the electrophilic attack. Docking results were discussed based on the different interactions between the ligands and proteins. The chloroquine derivatives are found to be a good inhibitor of COVID-19 virus and can, therefore, be effective in controlling this disease. We found that chloroquine phosphate was considered to be the best inhibitor of coronavirus pandemic. Maximum Cartesian force of chloroquine derivatives by using B3LYP/6-31G* level of theory. Table 2 : Calculated geometrical parameters for the chloroquine compound compared with the experimental ones by using B3LYP/6-31G* basis set. Table 3 : Calculated and observed geometrical parameters for the chloroquine phosphate. Table 4 : Calculated of some global reactivity descriptors of chloroquine derivatives. Table 5 : Docking results of chloroquine and chloroquine phosphate in COVID-19 protein. Table 6 : Amino acid residues-chloroquine interactions. Table 7 : Amino acid residues-chloroquine phosphate interactions. Severe outcomes among patients with coronavirus disease 2019 (COVID-19)-United States A novel Coronavirus outbreak of global health concern Epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in China India's indigenous idea of herd immunity: the solution for COVID A practical approach to the management of cancer patients during the novel coronavirus disease 2019 (COVID-19) pandemic: an international collaborative group Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Properties and molecular docking of antiviral to COVID-19 chloroquine combining DFT calculations with SQMFF approach Chloroquine and COVID-19, where do we stand Medecine et Maladies Infectieuses Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Lamballerie Of chloroquine and COVID-19 Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 Structural, docking and spectroscopic studies of a new piperazine derivative, 1-phenylpiperazine-1,4-diium-bis (hydrogen sulfate) Experimental and DFT studies on the molecular structure, spectroscopic properties, and molecular docking of 4-phenylpiperazine-1-ium dihydrogen phosphate Experimental, computational, and in silico analysis of (C8H14N2) 2 [CdCl6] compound Molecular docking studies, structural and spectroscopic properties of monomeric and dimeric species of benzofuran-carboxylic acids derivatives: DFT calculations and biological activities Searching potential antiviral candidates for the treatment of the 2019 novel coronavirus based on DFT calculations and molecular docking Combined experimental and theoretical studies on the molecular structures, spectroscopy, and inhibitor activity of 3-(2-thienyl) acrylic acid through AIM, NBO, FT-IR, FT-Raman, UV and HOMO-LUMO analyses, and molecular docking Properties and Reactivities of Niclosamide in Different Media, a Potential Antiviral to Treatment of COVID-19 by Using DFT Calculations and Molecular Docking Mind the gap Absolute hardness: companion parameter to absolute electronegativity Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density Becke's three parameter hybrid method using the LYP correlation functional A library for package independent computational chemistry algorithms Accelrys software inc GEMDOCK: a generic evolutionary method for molecular docking Proteins Structure cristallines et moléculaires de trois formes polymorphes de l'oestrone A solid-state dehydration process associated with a significant change in the topology of dihydrogen phosphate chains, established from powder X-ray diffraction UV and NMR) investigation on 1-phenyl-2-nitropropene by quantum computational calculations Quantum mechanical, spectroscopic and docking studies of 2-Amino-3-bromo-5-nitropyridine by Density Functional Method Natural localized molecular orbitals Efficient unbound docking of rigid molecules Ligand docking and binding site analysis with PyMOL and Autodock/Vina Synthesis, biological evaluation and molecular docking of novel series of spiro [(2H, 3H) quinazoline-2, 1′-cyclohexan]-4 (1H)-one derivatives as anti-inflammatory and analgesic agents Receptor-and ligand-based study of fullerene analogues: comprehensive computational approach including quantum-chemical, QSAR and molecular docking simulations Intermolecular interactions and molecular docking investigations on 4-methoxybenzaldehyde Using autodock for ligand-receptor dockingCurr