key: cord-0729235-vlneadzm
authors: Yadav, Pooja; Rana, Meenakshi; Chowdhury, Papia
title: DFT and MD Simulation Investigation of Favipiravir as an Emerging Antiviral Option against Viral Protease (3CL(pro)) of SARS-CoV-2
date: 2021-08-06
journal: J Mol Struct
DOI: 10.1016/j.molstruc.2021.131253
sha: 7a0cf37fbd7df270b445018fc29b39a412779abf
doc_id: 729235
cord_uid: vlneadzm

As per date, around 20 million COVID-19 cases reported from across the globe due to a tiny 125 nm sized virus: SARS-CoV-2 which has created a pandemic and left an unforgettable impact on our world. Besides vaccine, medical community is in a race to identify an effective drug, which can fight against this disease effectively. Favipiravir (F) has recently attracted too much attention as an effective repurposed drug against COVID-19. In the present study, the pertinency of F has been tested as an antiviral option against viral protease (3CL(pro)) of SARS-CoV-2 with the help of density functional theory (DFT) and MD Simulation. Different electronic properties of F such as atomic charges, molecular electrostatic properties (MEP), chemical reactivity and absorption analysis have been studied by DFT. In order to understand the interaction and stability of inhibitor F against viral protease, molecular docking and MD simulation have been performed. Various output like interaction energies, number of intermolecular hydrogen bonding, binding energy etc. have established the elucidate role of F for the management of CoV-2 virus for which there is no approved therapies till now. Our findings highlighted the need to further evaluate F as a potential antiviral against SARS-CoV-2.

Egypt, Turkey, Bangladesh) and USA, F was used everywhere as an emergency medicine to treat most of the COVID patients [18] [19] [20] . F also has received emergency approval by the drug controller general of India (DGGI) for treatment of COVID-19 in June, 2020 [19] . Favipiravir comes into its active form F-RTP after it undergoes phosphoribosylation. It is a target specific drug which acts as a substrate for RNA-dependent RNA-polymerase (RdRp) enzyme, which is mistaken by the viral enzyme as a purine nucleotide and so the viral protein allows it to inhibit by forming viral protein-RdRp complex form exonuclease (ExoN) [21] . During inhibition into the viral RdRp enzyme, facile insertion of F into viral RNA happens sparing human DNA. After inhibition, it leads to termination of the viral protein synthesis as it gets incorporated in the viral RNA strand preventing protein's further extension.

The envelope surface of the coronavirus is covered with spike glycoproteins (S), membrane proteins (M) and envelope proteins (E) [22, 23] . The main envelope of virus comprises a spiral nucleocapsid which is formed by genomic RNA and phosphorylated nucleocapsid (N) protein [24] . The S proteins of the virus initiate the attachment and entry to the host cells through the receptor binding domain (RBD) which is loosely attach to the virus surface [25] . To enter the host human cells, all coronavirus uses some key receptors. For SARS-CoV-2, the key receptor is angiotensin converting enzyme 2 (ACE2) [26] . After entering the host cell, airway trypsin-like protease (HAT), cathepsins and trans membrane protease serine 2 (TMPRSS2) split the S proteins of the virus and establish the penetration changes. So, development of targeted spike glycoprotein therapeutics against SARS-CoV-2 will definitely be a suitable option to combat COVID-19.

It is also reported that SARS CoV-2-RdRp complex is at least 10-fold more active than any other reported viral RdRp known [27] . For CoVs, the ExoN has been shown to remove certain nucleoside analogues (NAs) after insertion by RdRp into nascent RNA, which reduces their antiviral effects [28] [29] [30] . Despite this bad effect, several NAs like Favipiravir, Oseltamivir are currently being tested as anti CoV candidates. RdRp is one of the most intriguing and promising drug targets for SARS-CoV-2 drug development and F is one of such most effective RdRp inhibitor. The reason behind using an RdRp inhibitor like F to 3CL pro protein (6LU7) is that like all positive RNA viruses for CoV-2, RdRp (nsp12 protein) lies at the core of viral replication machinery. Due to its viral life cycle, lack of host homologous, high level of sequence and structural conservation nsp12 becomes an optimal target for therapeutics. But till now due to the lack of sufficient fundamental data, proper guide to design of an efficient antiviral therapeutics and their mechanism of action is not available. So RdRp inhibitors are chosen a promising target drugs since they are small sized NAs. It is reported that F can induces mutagenesis in vitro during influenza virus infection as it can inactivate the virus either by killing them or by changing their surface structure so the virus cannot be able to enter the host cells [31] . Though the proper interaction mechanism of mutagenesis is still unknown, we are expecting similar activity of F against SARS CoV-2 protein. We hope that F with its defined mode of action may well find a place as an anti RdRp component in combination therapies targeting corona viruses. Still the optimal dose of F is difficult to establish from the limited preclinical in vitro data. The above mentioned two way applicability of Favipiravir has motivated us to work on this specific antiviral drug against CoV-2 virus since it has recently received a lot of attention to treat Covid-19 patient [32] all over the World.

However, there is a scarcity of information on the structural effectivity, chemical reactivity prediction on F. Therefore, in the present work for the first time, the structural effectivity of the F molecule has been investigated by using density functional theory (DFT). In the present Covid-19 situation, molecular dynamics (MD) simulations have endorsed researcher to create rational scientific advances.

Advancement in this technology have made them an essential tool for scientists researching drug development [33] . Our in silico studies on structural analysis with the help of virtual screening, chemical analysis, molecular docking and MD on Favipiravir as ligand and 3CL pro main spike protease of CoV2 as receptor have established that COVID infections can be nullified by Favipiravir as it helps to shield the living host cell from the possible detrimental impact from CoV2 infection.

Favipiravir (T-705) is a synthetic prodrug (C5H4FN3O2), which is used in the antiviral activity of chemical agents against the influenza virus [31] . It has a good bioavailability (∼94%), 54% protein binding affinity. F-RTP binds to inhibits RdRp, which ultimately prevents viral transcription and replication [10, 30] . Virtual screening of the drug has done before the checking of inhibition capability. SWISS ADME software (https://www.swissadme.ch) and ADMET (https://vnnadmet.bhsai.org/) software were used for the virtual screening [34] . Drug-likeness rules like Lipinski's rule of five (Ro5), Veber's rule, MDDR-like rule, Egan rule, Ghose filter, Muegge rule etc., were used for preliminary drug screening [35] [36] [37] . For Drug preparation, the ligand in 'SDF' format was obtained directly from the PubChem (National Library of Medicine) (https://pubchem.ncbi.nlm.nih.gov/) and converted to 'PDB' format with the help of Auto Dock tools [38] . Molecular structure of the ligand was optimized by using DFT with the basis set 6-311G (d,p) [39] using the Gaussian 09 program [40] .

SARS-CoV-2 is a virus having positively sensed single stranded RNA. The protein structure of CoV-2 contains spike (S), membrane (M), envelope (E) and nucleocapsid (N) [41, 42] . The structures of CoV-2 virus and already known CoV virus is very similar [43] . So the identification process of (3CL pro ) of CoV-2 was appeared to be much faster [44, 45] . 3CL pro is located at the 3 ends, which exhibits excessive variability and can be treated as a potential target or anti-coronaviruses inhibitors screening [46] . In the present study, we have used 3CL pro proteases (6LU7) as main target protein of drug molecules.

The 3D structure of the 6LU7 was retrieved from the Protein Data Bank website (https://www.rcsb.org) [47] and existing water molecules available in the structure were removed (Figure 1 ). Polar hydrogen were added in protein structure and inbuilt ligand was removed from the protein structure with the help of Discovery studio 2020 [48] . All of the above steps were performed in AutoDock [31] , Molecular Graphics Laboratory (MGL) tools [49] . The output protein structure was saved in PDB format for further study.

All the theoretical calculations, including the optimization of ground state geometries were carried out using the Gaussian 09 program [50, 51] . The geometry of F was optimized, with density functional theory (DFT) using Becke3-Lee-Yang-Parr (B3) [52] exchange functional combined with the (LYP) [53] correlation functional with the standard 6-311G basis set. Excited state calculation of molecule was performed using time dependent DFT (TD-DFT). The frontier molecular orbital (FMOs) are simulated for the molecule using Koopman's theorem [54] . MEP surface mapped with electrostatic potential surface and atomic charges (Mulliken and natural) were derived by using optimized structure.

In computer-assisted drug designing, molecular docking is considered as the tool which helps in energy minimization and finding binding affinity between protein and ligand. In the present study protein-ligand interaction was studied by using the software used for Molecular docking is AutoDock 4.2 and AutoDock vina [38] . MGL tools were used for the preparation of protein and ligands for molecular docking. We have removed all the usual bound ligand present on the 3D structure PDB: 6LU7 protein. Reason for deleting the bound ligand present on the 3D structure of protein is that because of it ligand will not easily set in the pocket region and that will give incorrect results in docking. We have also removed all the Hetatoms present on the protein since they can block up binding sites and cause problems with protein-ligand interaction. The output structure of macromolecule is saved in pdbqt where G is binding affinity, R is universal constant and T is the room temperature (298 K).

For reliability of the docking results, we have performed docking for same protein-ligand pair with the help of another docking software Pyrx [55] . We have performed MD simulation for calculating various thermodynamics parameters like potential energy (Epot), root mean square deviation (RMSD) for backbone, root mean square fluctuation (RMSF) for protein Cα Solvent accessible surface area (SASA), intermolecular hydrogen bonds, and binding energy of the ligand: protein complex structure with the help of Linux based platform ''GROMACS 5.1 Packageˮ [56] with GROMOS43A2 force fields [57] .

According to the procedure followed for MD simulation, TIP3P water model has been used and 4Na + ions were added to maintain the neutrality of ligand: protein complex structure in a cubic box, with a buffer distance of 10 Å and volume as 893,000 A 3 . For energy minimization of complex, time varying (1ps-100000 ps) steepest descent algorithm with for 500,00 steps was used.

To calculate the interaction free energies for the protein: ligand complex structure (ΔGbind), the MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method [58] sourced from the Adaptive Poisson-Boltzmann Solver (APBS) and GROMACS packages have been used. To calculate ΔGbind, the snapshots at every 100 ps between 0 and 100000 ps (100ns) were collected. After completing the MD simulation of the complex using the single trajectory approach ΔGbind calculation generally initiates. For the bound protein: ligand complex ΔGbind can be given as:

Where,-TΔS is the conformational energy change due to binding, ∆ , is solvation free energy change, ∆ is the molecular mechanical energy changes in gas phase, ∆ is the covalent energy, ∆ is electrostatic energy, ∆ is Van der Waals energy changes. ∆ is the sum of ∆ , ∆ , and ∆ changes. While covalent energy is the combination of bond, angle and torsion and ∆ , is the sum of polar and nonpolar contributions.To calculate the binding energy the data was collected between 0ps and 100000 ps (100 ns). For RMSD and RMSF, we have run multiple simulations independently.

MD simulations and corresponding energy calculations have been computed in a single system using HP Intel Core i5 -1035G1 CPU and 8 GB of RAM with Intel UHD Graphics and a 512 GB SSD.

The most stable structure of F in the ground state was optimized using B3LYP/6-311G*(d,p) level of theory ( Figure 1 ). Different bond lengths (Å) and bond angles (°) of F are shown in the Table 1 . The ground state electronic energy of the optimized structure is -3813.169 Kcal/mol. F possess a very high value of dipole moment of 5.23 Debye due to its C1 point group symmetry. The high value of dipole moment may increase the bioactivity of the probe system [59] . Bioactivity is a significant property of a drug that promotes bonding or complex formation of drug with the target protein [60] . 

The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) plays an important role in the investigation of chemical stability/reactivity, and related optical properties of the molecules [61] . The energy gap (Eg) can be easily calculated by taking the difference between energy of HOMO and LUMO orbitals of the probe molecule. Table 2 shows the computed theoretical energies of HOMO (EHOMO) and the LUMO (ELUMO) orbitals. The value of Eg for F was computed as 4.029 eV ( Table 2 ). The ionization potential (IP) can be computed as -EHOMO and the electron affinity (EA) is computed as -ELUMO.

Different FMO related molecular parameters (global hardness (η), electronegativity (χ), chemical potential (μ) and electrophilicity (ω), and chemical softness (S)) of the Fare calculated by using the following formulae in the framework of Koopmans' theorem [54] :

We have observed a moderate value of Eg (4.029 eV) which suggest the chemical reactiveness and optically polarizable nature of F molecule. Using the values of IP and EA, one can calculate χ, η and ω parameters, which are helpful in analyzing the reactivity of the molecule. The calculated value of IP as 6.756 eV and EA as 2.727 eV indicate high reactivity of F [62] . Higher value of χ (4.741eV) also confirms the higher reactivity of F. Organic molecules can be classified on the basis of ω values [63] .

An organic molecule will be of minimal electrophiles if its ω value is less than 0.8 eV, moderate electrophiles with 0.8 < ω < 1.5 eV and strong electrophiles if its ω value is greater than 1.5 eV [64] . In the present case our probe molecule F has ω value as 5.58 eV, which represent its strong electrophile nature. Chemical potential of -4.741 eV also indicates the electron-withdrawing character of F [64] .

Chemical η value of a system measures the resistance to alter the electron distribution, which is associated with the reactivity of the system. All the FMO related parameters suggested the higher reactivity of F towards the target protein. Energy gap (Eg) 4.029

Ionization potential (IP) 6.756

Electron affinity (EA) 2.727 6.

Electrophilicity Index (ω) 5.58

Chemical Potential (μ) -4.741 8.

Electronegativity (χ) 4.741 9.

Softness (S) 0.496 10.

Hardness (η) 2.014

All values are in ev

Mulliken and natural charges play a significant role, for predicting the nucleophilic, molecular polarizability and electrophilic reactive regions of a certain molecule [65] . 

The MEP surface of the optimized molecule F is shown in the 

The theoretical UV-Vis spectrum of F is shown in the Figure 4 . The computed absorption excitation energies (E), and oscillator strength (f) are reported in Table 3 . According to results, the max appears at nm which is due to n→π* transition and a weak band at 283.08 nm due to π→π* transition. These electronic transitions correspond to the π→π* and n→π*, makes the probe system highly unstable, which confirms its ability of binding to the target protein. 

Among all of Drug likeness Ro5 rule or ''a rule of thumbˮ is the most important rule. The filters of Ro5 are followed by: Molecular weight less than equals to 500, H-bond donors less than equals to 5, H-bond acceptor less than equals to 10, MLOGP less than equals to 4.15 and molar refractivity between 30 and 140. Those drugs which follows the Ro5 with some required pharmacological properties can be used as potential candidate for vocally active drug in humans [34] . F follows the Ro5 so it can be proposed as chemical compound with compulsory pharmacological properties as a potential candidate for orally active drug in humans [34] . From the ADMET analysis, we can conclude that F has no cytotoxicity effect and no hERG (human Ether-a-go-go Related-Gene) Blocker can have the maximum suggested dose as 170 mg/day (SD2).

Different favorable poses for F and protein obtained from molecular docking with binding energy, According to the available crystal structure, SARS-CoV-2 CL pro has four binding pockets named as S1, S1', S2 and S4 within its protease that function as active sites. The active site is made up of the base protein's backbone and side chain residues. The S1 binding site is created by Phe-140, Asn-142, Ser- Table 4 ). For the same pose structure one hydrophobic interaction was observed for docked structure between 6LU7 (Residue: HIS 41,) and F ( Figure 5 , 

The comparison of minimum potential energy (Epot) of the stabilized structures of protein in its apo state with individually docked ligand compound have been done simultaneously ( Table 5 , SD 5a).

Protein in its apo state has an average Epot of -0. Table 5 , SD 5b, 5c, 5d. During simulation, the average distance between the atoms of the protein is calculated using RMSD

analysis. This analysis reveals information about protein/complex structure, stability, and equilibrium.

To identify the conformation stability and convergence of 6LU7 bound with F, Simulation result was Perfect similarity in RMSF values confirmed that F:6LU7 complex structure does not affected the protein backbone (Figure 7a ). The radius of gyration (Rg) tells us about the compressed nature of a complex structure or backbone receptor protein [70] . Variation of Rg value throughout the total-time trajectory (0 ps to 100 ns) showed that F: 6LU7 has quite stable and compressed structure. Rg of F: 6LU7 and apo 6LU7 show a perfect match having an average value of 2.18 nm with a fluctuation between 2.13-2.24nm (Figure 7b , Table 5 ).

Solvent accessible surface area (SASA) tells about the area of receptor contact to the solvents. The greater value of SASA means that more of the drug is inserted into the water. And lower the value of SASA means that more of the drug is covered by the protein means better complexation. The SASA value for apo protein was calculated between 30-35 nm 2 with a 33 nm 2 mean value however, for F:6LU7 complex structure the SASA value was observed between 6-10 nm 2 which satisfied the possibility of 20 better complexation of F drug with receptor 6LU7 (Figure 8a , Table 5 ). Stability of ligand: receptor protein complex structure is always dependent on the contribution of nonbonded interactions. To find the ligand binding affinities towards receptor protein, we have applied the MM/PBSA method to compute the binding energy of the complex structure formation. According to the applied method Van der Waal energy (Evdw) and electrostatic energy (Eelectrostatic) have been computed and are shown in Table   5 . For inhibitor F, the best binding affinity was observed for with the appearance of values of Evdw (-0.65±0.03 Kcal/mol) and Eelectrostatic (-0.17±0.01 Kcal/mol) ( Table 5 ). All the energies needed for ΔG are polar and nonpolar solvation energies which are shown in the also who are uqually effective towards the same protease in terms of their binding affinity ranges from -6 to -40 Kcal/mol. They are Chloroquine [71] , Hydroxychloroquine [10] , Nelfinavir [72] , Azithromycin [6] , Lopinavir [73] , Ritonavir [73] , Remdesivir [74] etc. Some of these drugs show better binding affinity and some also show less affinity towards 3CL pro protease-6LU7. (Figure 12 a, b) . The small change is position through the time scale was also verified by the resulting RMSD after structural superposition which was observed as 1.467 Å. results in a substantial change in the overall motion of 6LU7 with a compressed conformational space.

( Figure 13(a-c) ). The result also validate that F bound 3CL pro protein is more stable than the unbound protein. We have also examined the free energy landscape (FEL) against the first principal components PC (RMSD) to show the energy minima landscape of unbound protein and F bound 3CL pro protein ( Figure   14(a,b) ). The value of ∆G for both cases is 0 to 10 kcal/mol. The minimal energy area and size (shown in black) indicate the apo protein (6LU7) and F:6LU7 complex's stability. The stability of the protein and its related complex is indicated by smaller and more centred black patches.

Favipiravir, which was originally designed for influenza has recently attracted too much attention as an effective repurposed drug against COVID-19. Our present work represents the computational work on the applicability of F as an emerging antiviral option against SARS-CoV-2 pandemic. Different The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Graphical Abstract