key: cord-0986492-los6qnc5 authors: Shahab, Siyamak; Sheikhi, Masoome; Alnajjar, Radwan; Saud, Sultan Al; Khancheuski, Maksim; Strogova, Aleksandra title: DFT Investigation of Atazanavir as Potential Inhibitor for 2019-nCoV Coronavirus M protease date: 2020-10-17 journal: J Mol Struct DOI: 10.1016/j.molstruc.2020.129461 sha: ad3cb65a93faed6e7c8e3b78626a0011c4cdd128 doc_id: 986492 cord_uid: los6qnc5 Atazanavir (ATZ) is an antiviral drug synthesized. ATZ is being investigated for potential application against the Coronavirus 2019-nCoV. To find candidate drugs for 2019-nCoV, we have carried out a computational study to screen for effective available drug ATZ which may work as an inhibitor for the Mpro of 2019-nCoV. In the present work, the first time the molecular structure of ATZ molecule has been studied using Density Functional Theory (CAMB3LYP/6-31G*) in solvent water. The electronic properties, atomic charges, MEP, NBO analysis, and excitation energies of ATZ have also been studied. The interaction of ATZ compound with the Coronavirus was performed by molecular docking studies. Atazanavir with the brand name Reyataz among others is an azapeptide protease inhibitor (PI) and has been approved both by the FDA and the European Medicines Agency (EMA) for the treatment of HIV infectious disease [1] . Atazanavir (ATZ) has fewer restrictions rather than other classic PIs including offering a lower pill burden, a more favorable lipid profile, and a lower incidence of gastrointestinal symptoms [1] . ATZ drug may become a new option for first-line PIs or salvage therapy in patients with moderate experience with PIs. Atazanavir is a highly selective and effective inhibitor of the HIV-1 protease enzyme. Early development studies performed in the late 1990s confirmed that it blocked the cleavage of both gag and gag-pol precursor proteins in HIV-infected cells, leading to a release of noninfectious and immature viral particles [2] . Atazanavir is an azapeptide HIV-1 PI that prevents the formation of mature virions through the potent and selective inhibition of viral Gag and Gag-Pol polyprotein processing in HIV-1infected cells [3] . Atazanavir may cause side effects. Many side effects from HIV medicines, such as nausea or occasional dizziness, are manageable. See the Clinical Info fact sheet on HIV Medicines and Side Effects for more information. Some side effects of atazanavir can be serious. Serious side effects of atazanavir include changes in heart rhythm, severe rash, liver problems, and life-threatening drug interactions. (See section above: What are the most important things to know about atazanavir?). Other possible side effects of atazanavir include: mild rash, chronic kidney disease, Kidney stones. Contact your health care provider if you have pain in your lower back or lower stomach area, blood in your urine, or pain when urinating, gallbladder problems. Contact your health care provider right away if you develop symptoms of gallbladder problems (pain in your right or middle upper stomach area, fever, nausea and vomiting, or jaundice), diabetes and high blood sugar (hyperglycemia), changes in your immune system (called immune reconstitution inflammatory syndrome or IRIS). IRIS is a condition that sometimes occurs when the immune system begins to recover after treatment with an HIV medicine. As the immune system gets stronger, it may have an increased response to a previously hidden infection, Changes in body fat (lipodystrophy syndrome), Increased bleeding problems in people with hemophilia [4] [5] [6] . According to the openly published data, in 2019, a novel Coronavirus 2019-nCoV was found to cause Severe Acute Respiratory symptoms and rapid pandemic in China. On 13, 16, and 21 January, respectively, Thailand, Japan, and Korea confirmed the detection of human infection with 2019-nCoV from China [7] . Liu and co-workers have been suggested 10 drugs such as Colistin, Valrubicin, Icatibant, Bepotastine, Epirubicin, Epoprostenol, Vapreotide, Aprepitant, Caspofungin, Perphenazine as a candidate against 2019-nCoV coronavirus [8] . They have been studied the interaction of the mentioned drugs with the Coronavirus by molecular docking studies. To find candidate drugs for 2019-nCoV, we have performed a theoretical study for evaluating the usability of Atazanavir (C 38 H 52 N 6 O 7 ) drug as an inhibitor for the Mpro of 2019-nCoV. The molecular docking approach is used to model the interaction between a molecule and a protein at the atomic level, which allows us to characterize the behavior of molecules in the binding site of target proteins as well as to elucidate fundamental biochemical processes [9, 10] . We have recently suggested Triazavirin drug as a candidate against 2019-nCoV coronavirus [11] . We have been investigated the interaction of the mentioned drug with the Coronavirus by molecular docking studies. In this work, the first time the structure of the Atazanavir (ATZ) molecule has been investigated using Density Functional Theory (DFT: CAMB3LYP/6-31G*) in solvent water. The electronic properties, MEP and NBO analysis, excitation energies ATZ have also been calculated. The interaction of ATZ drug with the Coronavirus was performed by molecular docking studies. In the current study, the first conformational analysis was performed for the compound Atazanavir (ATZ). Then, the quantum chemical calculations have been carried out for the most stable conformation using the Density Functional Theory (DFT) method at CAMB3LYP/6-31G* level of theory [12] in solvent water by the Gaussian 09W program package [13] Preparation of the protein receptor we have started with a procedure in which have deleted all water molecules and ligands except for necessary cofactors. We have examined the protein for gaps and follow procedures for building and optimizing the missing loops. We have added hydrogens and optimize the hydrogen-bonding network. Finally, we have saved cleaned structure for docking. Since the Atazanavir (ATZ) molecule is flexible a conformation search was conducted first to obtain the minimal structure, the conformation search was done using the conformer distribution tool implemented in Spartan 16 software, molecular mechanics MMFF94 [19] was used with 10,000 conformers as a limit. Six conformers were identified as a minimum, further optimized at the PM6 level used to enhance the MMFF output. The energy difference was in 0.00 -12.86 kcal/mol range (Fig. 1 ). The obtained conformers with relative energies computed at PM6 in gas. In the next step, the most stable conformation of ATZ in the ground state was optimized using CAMB3LYP/6-31G* level of theory (Fig. 2) . The theoretical parameters such as Bond lengths (Å) and Bond angles (°) are shown in and Table 1 . The HOMO and LUMO orbitals are the frontier molecular orbitals (FMOs) that have an important role in chemical stability, optical properties, UV/Vis spectrum, and kinetic reactivity properties of the molecules [20] . The energy difference between HOMO and LUMO orbitals shows an energy gap (E g ) which is related to the hardness or softness of molecules. We obtained the theoretical energies of HOMO (E HOMO ) and the LUMO (E LUMO ) orbitals and the electronic properties of the ATZ using CAMB3LYP/6-31G* level of theory; the results are reported in Table 2 . the electron affinity (A=-E LUMO ). The global hardness (η), electronegativity (χ), electronic chemical potential (µ) and electrophilicity (ω), and chemical softness (S) parameters of the ATZ are calculated with the following equations [21] [22] [23] [24] : in which is reported in Table 2 . The density of states spectrum (DOS) of the ATZ is shown in Fig. 3 . atoms have the highest positive charge about rather than other hydrogen atoms due to the attachment to electron-withdrawing nitrogen (nitro group) and oxygen atoms (hydroxyl group). interaction between bonds and studying charge transfer in molecules [27] . The filled and empty NBOs and the stabilization energy (E (2) ) calculated from the second-order micro disturbance theory of the ATZ molecule are represented in Table 4 . (2) Energy of hyperconjucative interactions, b Energy difference between donor and acceptor i and j NBO orbitals, c F(i, j) is the Fock matrix element between i and j NBO orbitals. The electron delocalization from the electron donor orbitals to the electron acceptor orbitals represented a conjugative electron transfer process between them [28] . For each electron donor orbital (i) and electron acceptor orbital (j), the interacting stabilization energy E (2) associated with the delocalization i→j is computed according to the following equation [28] : (6) in which q i is the electron donor orbital occupancy, ε j and ε i are diagonal elements and F(i,j) is the off-diagonal NBO Fock matrix element [27] . The stabilization energy (E (2) ) shows the value of the participation of electrons in the resonance between atoms [27] . The greater E (2) value, the most intensive is the interaction between donor and acceptor orbitals, i.e. the more donation tendency from electron donors to electron acceptors and the most extent of conjugation of the whole molecule. NBO analysis has been performed for the ATZ molecule using CAMB3LYP/6-31G* level of theory. The selected intramolecular hyperconjugative interactions of the ATZ such as π→π*, π*→π*, σ→σ*, n→π* and n→σ* transitions are reported in Table 4 . According to obtained results, the important π→π* transitions of aryl rings is observed for π(C4- The theoretical UV spectrum of ATZ was calculated using the TD-CAMB3LYP/6-31G* method. The calculated absorption wavelength ( = 100-400 nm), excitation energies (E), oscillator strength (f) greater than 0.1, and the participating orbitals in the electronic transitions are reported in Table 5 . According to results, the  max appears at 253.70 nm and the oscillator strength f = 0.69 that is due to charge transfer of one electron into the excited singlet state S 0 →S 1 with the participation of three configurations including H→L (85%), H-2→L (2%), H→L+1 (3%). Excitation of an electron from HOMO to LUMO [H→L (85%)] is the main contribution for the formation of the absorption band at  max = 253.70 nm. As previously mentioned, the electronic transitions from HOMO to LUMO at the λ max are due to the contribution of pi (π) bonds and lone pairs including π→π* and n→π*. The calculated UV spectrum of the ATZ molecule is shown in 376 kcal/mol that shows the weak binding affinity between them and 2019-nCoV [8] . Molecular docking energy data for mentioned ligand and hydrogen bonding are presented in Table 6 and Fig. 10 . In this work, the quantum chemical calculations were carried out for the Atazanavir (ATZ) compound. The geometrical optimized bond lengths and bond angles were calculated theoretically. 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