Abstract
Boceprevir drug is a ketoamide serine protease inhibitor with a linear peptidomimetic structure that exhibits inhibition activity against 2019-nCoV main protease. This paper reports electronic properties of boceprevir and its molecular docking as well as molecular dynamics simulation analysis with protein receptor. For this, the equilibrium structure of boceprevir has been obtained by DFT at B3LYP and ωB97XD levels with 6-311+G(d,p) basis set in gas and water mediums. HOMO–LUMO and absorption spectrum analysis have been used to evaluate the boceprevir’s toxicity and photosensitivity, respectively. Molecular docking simulation has been performed to test the binding affinity of boceprevir with 2019-nCoV MPRO; which rendered a variety of desirable binding locations between the ligand and target protein’s residue positions. The optimum binding location has been considered for molecular dynamics simulation. The findings have been addressed to clarify the boceprevir drug efficacy against the 2019-nCoV MPRO.
1 Introduction
New coronavirus disease (COVID-19) posed a significant risk to public health worldwide, prompting the WHO to designate it a pandemic on March 11, 2020 [1]. In China, this new coronavirus was unearthed late in December 2019 and identified early in January 2020, and the International Committee on Taxonomy of Viruses (ICTV) designated this new coronavirus as “Severe Acute Respiratory Syndrome Coronavirus 2” (SARS-CoV-2) as the novel virus on February 11, 2020 [2, 3]. Distinct but genetically related this virus perhaps got its moniker from the one that caused the SARS outbreak in 2003. The novel disease was subsequently given the name “COVID-19” by the WHO [4]. More than 200 countries around the world have experienced a rapid spread of the virus [5]. Clinically important traits of COVID-19 can lead to various illness conditions, including fever, pneumonia, lung infections, difficulties in breathing, etc. Corona viruses are single-stranded RNA viruses with an envelope that infect a variety of vertebrates. The disease takes 4 days on average to incubate, with the maximum incubation period being no longer than 41 days [6]. The risk of death is higher in people who are older and have concomitant conditions such as hypertension, diabetes, and coronary heart disease [7].
In order to combat the new coronavirus pandemic brought on by the virus, inhibiting activity at the primary protease of SARS-CoV-2 is of major interest. The Mpro of SARS-CoV-2 and SARS-CoV are quite similar to each other, with 96 % of sequence similarity and a high degree of structural similarity respectively [8]. In fact, both proteases share a number of residues crucial for catalytic activity, substrate binding, and dimerization [9]. Similar to the approach adopted for the discovery of other inhibitors for coronavirus proteases [10, 11], the development of inhibitors for the Mpro of SARS-CoV-2 [8] focuses on inhibition of the active sites to interrupt viral replication [12]. Because the drug molecules can bind to other proteins having comparable active sites when they target the active site, it might cause off-target harm too [13]. Another significant issue is drug resistance, particularly when the active site may potentially change as a result of mutation. By broadening the range and selectivity of medications that can fine-tune protein function while avoiding some of the drawbacks discussed above, targeting an allosteric site proximal to the primary binding site offers an alternative approach [14]. An essential factor in the time-sensitive environment of COVID-19 is the added possibility for drug repurposing using this strategy, which focuses on binding at allosteric sites to speed up and lowers the cost of bringing new medications to the market [15, 16]. Furthermore, most of the drug compounds cannot make their appearance to the market due to their poor absorption, distribution, metabolism, excretion and toxic issues; which are commonly known as ADMET. Toxicity is defined as the condition in which substance shows adverse effect and can harm an organism. Reportedly it is responsible for 20 % of late stage drug discovery failures. In silico toxicity analysis, which does not require animal trails and is quick and inexpensive, can be used to justify preclinical drug prediction. Many anticancer therapeutic drugs are effective for cancer treatment but their use is limited because of their toxicities. To improve the therapeutic index and to reduce the side effects, researchers are focused on developing nanoscale anticancer drug carriers [17], [18], [19].
In order to target various viral proteases and the proteasome, researchers chose a cluster of 18 chemical compounds after discovering that the Mpro of the SARS-CoV-2 has a high degree of similarity with the other CoV Mpro; and performed in vitro fluorescence resonance energy transfer (FRET) enzymatic assays at a single concentration to screen those chemical compounds [1]. Following those two inhibitors, boceprevir and GC376 were discovered, which effectively reduce enzyme activity. In combination therapy, the direct-acting antiviral drug boceprevir is used to treat chronic hepatitis C, a liver infection brought on by the hepatitis C virus [20]. In view of these facts the current investigation examines inhibitory activity of boceprevir against the 2019-nCoV main protease (https://www.rcsb.org/structure/7BRP). In order to check the reactivity, toxicity, and active sites of the drug molecule, DFT approach has been employed. The tested drug has been subjected to molecular docking and molecular dynamics (MD) simulations to check the stability of its binding to the protein.
2 Computational details
The optimization of geometry of boceprevir molecule has been performed employing B3LYP and ωB97XD functionals with 6-311+G(d,p) basis set [21], [22], [23], [24], [25], [26], [27], [28]. Following the optimization procedure, the drug molecule’s electronic properties, including its molecular electrostatic potential (MEP) surface, highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), have been calculated.
UV sensitivity of the drug molecule has been studied using TD-DFT method using both B3LYP and ωB97XD techniques at the same level of basis set. All computations have been performed on Gaussian16W [29] program and visualized on GaussView6.0 software [30]. The mathematical details for calculating electronic and global parameters can be found in literature [31], [32], [33], [34].
Molecular docking is regarded as a technology that aids in energy minimization and determining the binding propensity between a protein and a ligand in computer-assisted drug creation. For the development of drugs using a structure-based approach, molecular docking is a key technique. The goal of docking, as stated at the outset, is to anticipate the most advantageous ligand-target spatial arrangement and to quantify the associated complex free energy. However, precise scoring systems are still difficult to come across. In this study, the equilibrium structure as obtained from B3LYP/6-311+G(d,p) technique has been used for molecular docking with 2019-nCoV MPRO (PDB ID: 7BRP) that has been performed on SwissDock web server [35]. The various ways of binding of the drug boceprevir to 2019-nCoV MPRO residues have been visualized using the UCSF Chimera software tool [36].
The stability of the proposed compound’s active site binding to the receptor has been investigated using molecular dynamics simulation, and the interaction between the inhibitor and receptor has rigorously been examined. For this, the NAMD program [37] has been used to run the MD simulation for 100 ns. The simulation was run using CHARMM general force field (CGenFF) with the box size set to 74.93 Å × 69.91 Å × 69.58 Å [38]. The VMD software tool has been used to visualise the NAMD data [39]. The new models were created and tested using molecular mechanics generalized-born surface area (MM/GBSA) computations, which calculated binding free energy (ΔG) of protein-ligand complex based on molecular dynamics simulation paths and compared them with experimental binding data [40]. The MM/GBSA computation with single and multi-MD trajectory approaches on a solvated complex is shown graphically in Figure 1. In the present investigation, we use multi-MD trajectory approach.
Diagram illustrating the MM/GBSA calculation on a solvated complex.
In Figure 1, ΔEMM denotes a change in the energy of the molecular mechanics (MM) in the gas phase. Three terms are parts of the ΔEMM: the van der Waals energy change (ΔEvdW), the electrostatic energy change (ΔEelec), and the internal/covalent energy change that includes bond, angle and dihedral energies (ΔEint). Polar and nonpolar components combine to form the change in solvation free energy (ΔGsol). The generalized-born (GB) model estimates the polar contribution ΔGGB, and the solvent accessible surface area (SASA) model typically calculates the nonpolar component ΔGSA. Further, because it takes too long and calculations are done for the same chemical sequence of ligands, the entropy change, upon ligand binding, −TΔS is frequently overlooked in MM/GBSA calculations.
3 Results and discussion
3.1 Toxicity and photosensitivity analysis of boceprevir drug
In this study, DFT/B3LYP/6-311+G(d,p) and DFT/ωB97XD/6-311+G(d,p) approaches have been used to optimize the molecular structure of boceprevir drug. The optimized molecular structure of boceprevir as obtained from B3LYP technique is depicted in Figure 2. Figure 3 illustrates the molecular electrostatic potential (MEP) scanned at the B3LYP/6-311+G(d,p) level of theory to predict the reactive sites for electrophilic and nucleophilic attack. The maximum negative area (in red) and maximum positive area (in blue) stand for electrophilic and nucleophilic attack respectively. The zero potential region is symbolised by green color. The HOMO, LUMO and energy gap of boceprevir drug molecule are listed in Table 1. The reactivity, electrophilicity, and toxicity of the drug molecule have been examined. Table 2 displays the ionization potential, electron affinity, and global reactivity descriptors derived from both the techniques. A common quantum mechanical description can be given in terms of HOMOs and LUMOs energies. Here LUMO defines the simplest path for the addition of new electrons to the system, whereas HOMO signifies the energy distribution and energy of the least firmly bound electrons in the molecule. Obviously there exists a connection between HOMO energy and toxicity because HOMO energy is typically associated with a chemical inclination to donate electrons [41]. A molecule with high HOMO energy makes it possible for a suitable receptor molecule to deliver low energy electrons to the vacant molecular orbital. The LUMO energy, on the other hand, measures a molecule’s capacity to accept electrons; the lower the LUMO value, the more probable the molecule is to do so. While determining the chemical reactivity of drug molecules or ligands, HOMO and LUMO provide useful information [42, 43]. Charge transfer inside the molecule, which is critical in the production of chemically bound adducts causing cancer, is ascertained by the chemical reactivity descriptors [44]. These descriptors also accurately predict site selectivity via nucleophilic and electrophilic attack. The HOMO energy of the boceprevir with B3LYP functional comes out to be −6.568 eV while −8.656 eV from the ωB97XD functional. Despite the fact that both the approaches generally yield high HOMO energy, the ωB97XD approach provides relatively high value of HOMO energy. On the other hand, for LUMO energy reverse situation is observed (Table 1). This implies that the drug boceprevir is anticipated to function as an appropriate receptor molecule to transport low energy electrons to the open molecular orbital. Results for global hardness and electrophilicity index are shown in Table 2. The ability of an electron density to withstand deformation is measured by global hardness. Inferentially, a molecule becomes less reactive as it becomes harder. The global hardness of boceprevir drug is low; hence its reactivity to other chemical/biological species is high.
Optimized geometry of boceprevir obtained at B3LYP level with 6-311+G(d,p) basis set.
MEP surface of boceprevir computed by B3LYP/6-311+G(d,p) method.
HOMO energy (EHOMO), LUMO energy (ELUMO) and orbital energy gap (∆E) of boceprevir molecule as computed by B3LYP/6-311+G(d,p) and ωB97XD/6-311+G(d,p) methods in gas and water medium.
| Orbital Energy | In gas | In water | ||
|---|---|---|---|---|
| B3LYP | ωB97XD | B3LYP | ωB97XD | |
| EHOMO (eV) | −6.568 | −8.656 | −6.794 | −8.884 |
| ELUMO (eV) | −2.655 | −0.533 | −2.637 | −0.526 |
| ∆E (eV) | 3.913 | 8.123 | 4.157 | 8.358 |
Global reactivity descriptors and thermal parameters of boceprevir molecule.
| Global reactivity descriptors | B3LYP/6-311+G(d,p) | ωB97XD/6-311+G(d,p) | ||
|---|---|---|---|---|
| In gas | In water | In gas | In water | |
| Ionization potential (eV) | 6.568 | 6.794 | 8.656 | 8.884 |
| Electron affinity (eV) | 2.655 | 2.637 | 0.533 | 0.526 |
| Electronegativity (eV) | 4.611 | 4.715 | 4.594 | 4.705 |
| Electronic chemical potential (eV) | −4.611 | −4.715 | −4.594 | −4.705 |
| Global hardness (eV) | 1.956 | 2.078 | 4.061 | 4.179 |
| Global softness (eV−1) | 0.511 | 0.481 | 0.246 | 0.239 |
| Electrophilicity index (eV) | 5.435 | 5.349 | 2.598 | 2.648 |
One of the most frequent adverse drug effects involving the skin is photosensitivity. While considering the underlying causes and mechanisms, drug-induced photosensitization can be divided into photoallergic and phototoxic reactions. Drug-induced photosensitivity responses can occur and are influenced by both medication characteristics and UV–vis light exposure [45]. Drugs that cause photosensitivity are radiation-absorbing substances. Radiations in the visible and ultraviolet regions become significant in considering the issue of drug-induced photosensitivity. Visible wavelengths can affect structures in the epidermis, dermis, and subcutis, and demonstrate deep skin penetration [46]. The summary of the various mechanisms and processes that contribute to a photosensitive response of the reaction is shown in Figure 4(a). The UV–visible spectra of boceprevir as computed by TD-DFT/B3LYP and TD-DFT/ωB97XD with 6-311+G(d,p) techniques in gas and water mediums have been depicted in Figure 4(b). Figure 4(c) depicts electronic transitions in several molecular orbitals of the boceprevir molecule as acquired using the B3LYP/6-311+G(d,p) technique in water medium. The absorption wavelengths, obtained using B3LYP functional, lie in the visible range of the electromagnetic spectrum in both the media. The maximum absorption wavelength for the first, second and third excited states are located at 415.27, 355.68, and 347.96 nm, respectively, in gas phase while in water medium the respective absorption wavelengths are observed at 403.48, 329.61, and 323.04 nm for these states. The maximum absorption wavelength calculated by B3LYP method is in gross agreement with experimental value (λmax = 415 nm) reported in the literature [47]. The excitation energies corresponding to these states are 2.985, 3.485, and 3.563 eV in gas phase, while 3.073, 3.761, and 3.838 eV, respectively, in water medium. Due to electronic transitions taking place between HOMO and LUMO energy levels, the absorbed radiation causes a number of photo-induced biological reactions. For the first excited state, the maximum electronic transition has been observed from HOMO-2 to LUMO with molecular orbital (MO) contribution of 82.99 % (87.72 % in water). The maximum electronic transition between HOMO-1 and LUMO occurred in the second excited state, with a MO contribution of 68.07 % (57.40 % in water). The third excited state has maximum electronic transition from HOMO to LUMO level with MO contribution of 71.55 % (59.62 % in water). First, second, and third excited state wavelengths from the ωB97XD functional are found at 378.44, 253.59, and 233.56 nm, respectively, in gas phase while at 370.36, 245.77, and 227.85 nm in water medium, respectively. In gas phase the respective excitation energies correspond to 3.276 eV (3.347 eV in water), 4.889 eV (5.044 eV in water), and 5.308 eV (5.441 eV in water). Evidently absorption wavelength of first excited state, as computed by B3LYP technique in both the media lies in the visible range. The absorption wavelength of first excited state obtained from the ωB97XD method is almost in the visible spectrum. The remaining two wavelengths obtained from both the techniques lie in the UV range. These results suggest that the drug boceprevir is sensitive to the UV and visible range of radiation and hence comes into the photosensitive zone. This outcome is also validated by other reports (https://www.drugs.com/sfx/boceprevir-side-effects.html#refs). Therefore, while administering the medicine boceprevir, some safety measures must be taken into account.
Representation of the mechanism of photosensitivity induced by UV–visible radiations: (a) pictorial demonstration of drug-induced photosensitivity, (b) UV–visible spectra of boceprevir and (c) electronic transitions in various molecular orbitals of boceprevir drug computed at B3LYP/6-311+G(d,p) level in water medium.
3.2 Ramchandran plot and molecular docking study
There are two main regions of residue conformations that are permitted in the Ramachandran plot. These correspond to the two prominent secondary structures, alpha-helix and beta-sheet, and are depicted as the alpha-region and beta-region, respectively. Figure 5 shows the Ramachandran plot for various angle combinations (Phi–Psi) for the 7BRP protein receptor, created by the PROCHECK web server [48] which is in accordance with the earlier study [49]. Each conformation of the protein residue’s main chain is shown by a light blue square. The 7BRP protein contains a total of 602 residues in which most favored regions (red colour) contain 471 residues and are represented by A, B, and L (Figure 5). Accordingly, these regions correspond to the beta-strand, the alpha-helix, and the left-handed alpha-helix conformations. The additional allowed regions are represented by a, b, l, and p which include 48 residues (yellow color). The transition from the most to the least advantageous conformation is then indicated by the light-yellow color. The area where majority of points are concentrated (marked with B) is highlighted in red.
Ramachandran plot of 7BRP. Squares stand in for non-glycine residues, and triangles for glycine residues. Red colour is used to identify non-glycine residues that occur within zones with lax restrictions. There were no non-glycine residues that fell into forbidden areas.
Because molecular docking may be used to simulate the atomic-level interaction between a tiny molecule and a protein, it works better for drug development. This technique enables us to characterise action of tiny molecules at target protein binding locations and to better understand basic biological and chemical processes [50, 51]. The goal of molecular docking is to anticipate the structure of the protein-ligand complex using computational techniques. Here, molecular docking of boceprevir drug with the 2019-nCoV MPRO receptor (PDB ID: 7BRP) has been carried out. There are five most preferred binding poses observed for boceprevir and protein (7BRP) complex; which are illustrated in Figure 6. With same binding energy of −9.513 kcal/mol, the residues GLY143(HN) with LIG(O10) and GLU166(HN) with LIG(O3) form the most stable conformation (Figure 6a). The respective distances between the residue and the ligand are 2.194 Å and 1.904 Å. The second most preferred binding interaction has been established between the residue GLY143 (HN) and LIG (O12) with binding energy of −9.345 kcal/mol at a separation of 2.203 Å. Residues HSD164(O), GLU166(HN), and GLU166(HN), respectively, bind to LIG(H35), LIG(O3), and LIG(O3) with corresponding energy of −9.274, −9.145, and −9.120 kcal/mol in the third, fourth, and fifth binding modes successively (Figure 6b). These observations elucidate that GLU166 and GLY143 are the essential residues in the ligand-7BRP complex, engaged in hydrophobic interactions.
The optimal binding conformation of boceprevir with 2019-nCoV MPRO receptor (7BRP), in which ligands (boceprevir) are depicted as sticks and 7BRP is displayed as a ribbon colored by residue: (a) most preferred site @1, and (b) preferred site @ 2, 3, 4 and 5.
3.3 Molecular dynamics simulation
MD simulation was run for 100 ns to assess the steric refinement and stability of the boceprevir drug. For this, best binding pose of protein-ligand complex was selected and the MD simulation was started on NAMD program. Following the molecular dynamics simulation, the trajectory files were produced, and numerous analyses such as RMSD, RMSF, radius of gyration (R g ), and SASA variations, were performed along with electrostatic and van der Waal’s energy variations.
3.3.1 Analysis of geometrical stability
The consistency of the system during the MD simulation caused changes in the protein backbone, which can be identified using RMSD [52]. Higher RMSD value shows that the protein’s backbone suffered structural conformation changes during the simulation period, whereas lower RMSD value indicates that the protein is highly stable. To evaluate the conformational constancy of the complex during the simulation, the RMSD value of the complex was carried out. As seen in Figure 7, the RMSD pattern across protein and complex differs significantly. The RMSD fluctuations of protein increase linearly up to 35 ns and after that get saturated throughout the simulation with average value of 1.95 Å. The RMSD fluctuations for the complex, on the other hand, saturates at 10 ns for entire time steps having mean value of 1.75 Å. Inferentially, boceprevir forms a stable complex with the 7BRP receptor, as evidenced by the mean value of RMSD of complex being less than 2.0 Å [53].
RMSD of the 7BRP protein’s backbone atoms with boceprevir.
3.3.2 Analysis of geometrical flexibility
To ascertain whether the inhibition of the ligand had any impact on the dynamic behavior of the residue, the RMSF value of the boceprevir-7BRP complex is determined. Numerous oscillating behaviors are noticed in the complex as shown in Figure 8. Evidently, residues SER301 and LEU351 exhibit higher fluctuations with values of 2.21 Å and 2.95 Å, respectively, while rest of the residues reflect fluctuations below 2.0 Å. A fluctuation value below 2.0 Å is considered acceptable for small proteins. Thus, according to RMSF analysis, the amino acids in the protein for the complex bear a little conformational variability.
RMSF of the 7BRP in the boceprevir complex.
3.3.3 Analysis of geometrical compactness
The mass-weight root mean square distance of a group of atoms from their shared center of mass is used to define the radius of gyration (R g ). R g gives information about the protein’s overall dimensions. R g , thus, plays a crucial role in describing the dynamic stability and compactness of the whole protein system. Over the course of 100 ns simulations at 310 K, the R g was plotted for protein-ligand complex against time; which is depicted in Figure 9. Obviously fluctuations of R g for the complex remain constant as compared to the protein during the entire simulation time with mean value of 25.95 Å, demonstrating that the simulation paths for MD run of the selected ligand represent that the residues of amino acids are constant throughout the simulation. As a result, there is no discernible difference between the compound’s initial and final values, according to the finding. Consequently, it may be established that the protein backbone linked to the compound is stiff.
Radius of gyration (R g ) for protein backbone atoms during simulation with boceprevir.
3.3.4 Analysis of hydrogen bond interaction
Analysing the MD trajectories allowed us to determine how many hydrogen bonds were there between the ligand and protein complex. The maintenance of protein structure depends strongly on hydrophobic interactions and H-bonding. In addition, the shape of the protein can change as a result of hydrogen bonding between amino acids. Figure 10(a) shows the total number of hydrogen bonds that are created when the ligand and 7BRP are combined. From Figure 10(b) it has been observed that, the complex exhibits hydrogen bonding ranging from 0 to 4 between the residues ARG40 and ASP187 with maximum occupancy of 98.30 %. For the same range, the H-bonding between the residues ARG4-GLU290, ARG131-ASP289, and VAL114-TYR126 have been found with the donor-acceptor occupancies of 97.41 %, 96.51 %, and 90.61 %, respectively. The hydrogen bonding between the residues TRP31 and CYS16 has the range of 0–2 with donor and acceptor occupancy value of 92.81 %.
Pictorial representation of hydrogen bonding interactions: (a) total hydrogen bond numbers formed between 7BRP residues and boceprevir and (b) hydrogen bond numbers between amino acid residues in protein-ligand complex.
3.3.5 Analysis of solvent accessible surface area
Solvent-accessible surface area, or SASA, is the portion of a biological molecule that a solvent can access. It is employed to gauge how much an amino acid is exposed to its surroundings. Protein structures that are dispersed have a higher SASA value and those that are compact have a lower SASA value. A change in the protein’s structure is indicated by an increase or reduction in the SASA score. For protein-ligand complex, the SASA value calculated with time has been shown in Figure 11. The SASA value of protein increases for the entire step of the simulation, while in case of complex it increases up to 30 ns and after that gets saturated with mean value of 44,896 Å2. The increase in SASA value of protein may be due to the mutation that results in a conformational change [54]. Thus, the stable SASA result of the complex conforms very well with that of the RMSD and radius of gyration outcome.
Solvent accessible surface area (SASA) variation throughout 100 ns of simulation.
3.3.6 Analysis of binding free energy
The determination of free energy using MD simulation technique is the best way to demonstrate the binding affinity of certain compounds. During the final 40 ns of the MD paths in the current study, the binding free energy has been determined by MM/GBSA method (Table 3). The findings imply that all the systems (ligand/protein/complex) have electrostatic energies greater than van der Waals energies, indicating polar surroundings around the binding site. The average values of electrostatic energy of protein, ligand and complex are −17,452.23, −141.61, and −17,707.01 kcal/mol, while the corresponding average values of van der Waal energy are −1486.20, −3.08, and −1401.27 kcal/mol, respectively. The protein-ligand complex (boceprevir-7BRP) has a binding free energy of −25.16 kcal/mol, which indicates that the ligand interacts with the active site of residue mostly through H-bonds and hydrophobic interactions. The electrostatic and van der Waal energy trajectories of protein, ligand, and complex are depicted in Figure 12.
Average values of electrostatic, van der Waal and free energies of protein, ligand, and complex along with resultant binding free energy.
| Average energy (kcal/mol) | Free energy (kcal/mol) | ||
|---|---|---|---|
|
|
−17,452.23 | G protein | −18,938.43 |
|
|
−1486.20 | ||
|
|
−141.61 | G ligand | −144.69 |
|
|
−3.08 | ||
|
|
−17,707.01 | G complex | −19,108.28 |
|
|
−1401.27 | ||
| Resultant binding free energy (ΔG) of the complex | −25.16 | ||
Electrostatic and van der Waal energy of protein (7BRP), ligand (boceprevir) and protein-ligand complex during 100 ns MD simulation.
4 Conclusions
This paper reports an in-silico approach regarding inhibition activity of boceprevir drug against 2019-nCoV MPRO receptor. The MEP surface elaborates lucidly the electrophilic/nucleophilic sites of the boceprevir molecule. The HOMO–LUMO energy gap of the drug is slightly increased in water as compared to gas phase. Its value obtained by B3LYP functional is 3.913 eV (gas phase), indicating its moderate chemical reactivity and kinetic stability. The photosensitivity of boceprevir is evidenced by its UV–vis spectrum showing maximum absorptivity at 227.85 nm and 253.59 nm. The Ramachandran plot of the 7BRP receptor supports model skeleton structure of protein. Molecular docking illustrates that LIG(O12) complexed with GLU166(HN) receptor of the 7BRP protein is the most favored having energy of −9.513 kcal/mol at ligand-receptor optimum distance of 1.904 Å. Consideration of the preferred binding sites between the drug and protein, leads to the formation of three prominent hydrogen bondings. Molecular dynamics simulation indicates strong hydrophobic interactions. The binding free energy calculated by MM/GBSA method for the complex comes out to be −25.16 kcal/mol, indicating a good binding affinity of boceprevir and its stability with 7BRP protein receptor. The study may be of help in exploring treatment options for future COVID-19 outbreak prevention.
Acknowledgements
Authors are grateful to Prof. S. N. Tiwari, Department of Physics, D.D.U. Gorakhpur University, Gorakhpur, for his insightful comments and helpful discussion. D. Sharma expresses gratitude to UGC, New Delhi, India for financial support in the form of the Start-Up Project [F.30-505/2020(BSR)].
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Research ethics: No human or animal participation in this work.
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Author contributions: G.T. performed the DFT and molecular docking calculation, helped in formal analysis, wrote the first draft of the manuscript; M.S.C. developed the idea, formal analysis, and performed the MD simulation; D.S. developed the idea, formal analysis, wrote the first draft of the manuscript, carefully examined the results, discussion and final proof of the text. The final version of the manuscript was reviewed, assembled and approved by all of the authors.
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Competing interests: All authors declared that there is no conflict of interest.
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Research funding: No funding was received for this research.
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Data availability: Data will be available/provided on a reasonable request.
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