Abstract
Although the severity of the spread of corona virus has recently decreased. On this day, there is no available effective medication established to treat COVID-19. Combination drug therapy has been recently gained new momentum as an important platform to design and develop several anti-infective agents. In this study, the last FDA-authorized covid-19 therapy ritonavir-boosted nirmatrelvir (Paxlovid) have been the subject to investigate their potential synergetic efficiency in comparison with some selected antiviral drugs through molecular multiple docking, density functional theory (DFT) calculations, physicochemical and pharmacokinetics predicted properties. The multiple docking results revealed the most synergistic affinities for nirmatrelvir with nitonavir drugs against the main protease (Mpro) of omicron variant. LogP, H-bond acceptor and H-bond donor were found as the powerful predicted parameters of nirmatrelvir and ritonavir synergetic drugs. It has been well established that chemical reactivity descriptors displayed the same values for these both drugs. The pharmacokinetic parameters did not exhibit any correlation with the combined compounds affect.
Keywords: Nirmatrelvir/Ritonavir, Multi docking, Synergetic drugs, DFT, ADME
Graphical abstract
1. Introduction
The severe acute respiratory syndrome (SARS-CoV) outbreak started in 2003 in China followed by the second outbreak of the Middle East respiratory syndrome (MERS-CoV) in 2012 in Saudi Arabia. Again the SARS-CoV 2 infection was started in late the year 2019 which has been named as a novel coronavirus (COVID19) on January 12, 2020 which attacks the immunity system and the immune system breaks down in the worst condition [1,2]. Up to now, several variants have been identified or are under investigation. Omicron, Delta, Alpha, and more … [3,4]. Many treatment strategies have been adopted and many medications are authorized for emergency use to medicate COVID-19, both inside and outside of the hospital. Among them, favipiravir, ribavirin, lopinavir, ritonavir, darunavir, arbidol, chloroquine, hydroxychloroquine, dememexasone and azithromycin [[5], [6], [7]], some others are confirmed clinically to be effective in eliminating SARS-CoV-2 and reducing its symptoms [8]. In October 2020, remdesivir (Veklury) became the first drug approved by the Food and Drug Administration (FDA) to treat COVID-19, an antiviral drug was previously developed against Ebola virus disease in 2016 [9,10]. On December 22, 2021, the FDA authorized an oral antiviral pill, called paxlovid a co-packaged combination of nirmatrelvir and ritonavir that inhibits the main protease Mpro of SARS-CoV-2 destined for mild and moderate COVID-19 patients [[11], [12], [13]]. Furthermore, a combination of two or more drugs to treat a disease, also known as drug combination therapy [14], has demonstrated their effectiveness against a variety of complex health issues like cancer, HIV and cardiovascular diseases [15,16]. Additionally, an antiviral synergy has been previously illustrated for the treatment of hepatitis C virus, Ebola virus, Zika virus and human cytomegalovirus [[17], [18], [19]]. This study aimed to focus on the nirmatrelvir/ritonavir combination efficacy against the recently emerged omicron variant of the SARS-CoV-2 virus, compared with some drugs mentioned in the WHO's clinical protocol of COVID-19 treatment since the appearance of this world pandemic, such as remdesivir, lopinavir, favipiravir, chloroquine and molnupiravir, by applying individual and multiple docking. Interestingly, we also especially inspected the synergistic drug combinations, based on their computed bioinformatics and chemoinformatics parameters, which included physicochemical, pharmacokinetic properties and global reactivity descriptors.
2. Materials and methods
2.1. Receptor and ligands preparation
The main protease (Mpro) of SARS-CoV-2 omicron variant (PDB code: 7TOB) was selected as drugs target, its crystal structure was downloaded from the Protein Data Bank (https://www.rcsb.org/).The water molecules and heteroatoms of protein were removed followed by the addition of hydrogen atoms. The active site pocket of the receptor found out by the MOE-Site finder tool. The selected drugs were collected from the public chemical database (https://pubchem.ncbi.nlm.nih.gov/), inputted into MOE software and subjected to 3D protonation and energy minimization. The PyRx tool of AutoDock was used to perform the multidrug docking simulations.
2.2. Molecular docking process
Above all, the docking simulations was performed on the Molecular Operating Environment (MOE) (2014.0901) software package [20]. The MMFF94 force field was applied to minimize the protein structure. Triangle matcher algorithm (placement stage) and scored by London dG scoring function (Default parameters). Ten poses were generated for each ligand, the best five poses of them were submitted to the refinement stage to calculate the final score with GBVI/WSAdG scoring function. The 2D ligand-protein interactions were visualized using the MOE ligand interactions. In the second step, Autodock vina 4.2 [21] in PyRx 0.8 was used to compute the multiple docking. Initially, the imported structures of drugs in SDF format was minimized and converted to PDBQT format. The grid box parameters were maximized to the entire protein surface (“blind” docking). Structural analysis of the ligand-protein complexes were performed by using PyMOL and Discovery Studio software [22,23].
2.3. Physicochemical and pharmacokinetic predicted properties
The prediction of the physicochemical properties, molecular weight (MW), lipophilicity (LogP), H-bond donor (H-don), and (4) H-bond acceptor (H-acc) and TPSA) associated with Lipinski's Rule of Five were performed by using ADMETlab 2.0 online sever (https://admetmesh.scbdd.com/service/screening/cal). The pharmacokinetics ADME (absorption, distribution, metabolism, and excretion) properties, Blood-Brain Barrier (BBB), Skin Permeability (cm/s), GI absorption, Water solubility, Caco2 permeability, Intestinal Absorption (human) were acquired from SwissADME (http://www.swissadme.ch/) and pkCSM (http://structure.bioc.cam.ac.uk/pkcsm) web scientific platforms.
2.4. Density functional theory (DFT) calculations
Density functional theory (DFT) is a quantum-mechanical (QM) method has shown great significance in computational physic and chemistry. It was used to calculate the electronic properties of molecules, by employing the B3LYP (Becke three parameters hybrid functional with Lee–Yang–Perdew correlation functionals) and the 6–311G(d) atomic basis set [24], via the Gaussian 09 program package [25]. The results were visualized using Gaussview 06 software [26].
3. Results and discussion
3.1. Docking individual analysis
The crystal structure of the SARS-CoV-2 Omicron main protease (Mpro) was determined at 2.05 Å and presented in the Fig. 1 .
Fig. 1.
Crystal structure of main protease (Mpro) of SARS-CoV-2 omicron variant (PDB ID: 7TOB).
The docking score and validate RMSD trajectories values of the seven proposed drug against Mpro receptor are depicted in Table 1 . All the molecules showed interaction within the binding sites of protein, and they displayed a binding energy in the range of −8.63 kcal/mol to −6.09. Ritonavir exhibited superiority in binding over the other selected compounds with −8.63 kcal/mol followed by lopinavir (−8.21 kcal/mol), nirmatrelvir (−7.89 kcal/mol) with RMSDs of 2.2570 Å, 1.4318 Å and 1.5417 Å respectively. Near this binding score energy level, remdesivir revealed −7.70 kcal/mol. Favipiravir (−6.71 kcal/mol) and hydroxyhloroquine (−6.09 kcal/mol) exhibited lower activity. Instead, molnupiravir displayed 3.3472 of RMSD over 3 Å which indicates which indicate inappropriate value, therefore was not taken in consideration in the next investigation.
Table 1.
The docking result of selected drugs against target main protease (Mpro).
| Drugs | S | RMSD | Ligand atom | Interaction bond | Receptor residue |
|---|---|---|---|---|---|
| Nirmatrelvir | −7.89 | 1.6176 | N | H-donnor | Glu 166 |
| O | H-acceptor | ||||
| Ritonavir | −8.63 | 1.8505 | π-H | Arg 279 | |
| Remdesivir | −7.70 | 1.6114 | O N |
H-donnor | Glu 166 |
| H-acceptor | His 163 | ||||
| π-H | Asn 142 | ||||
| π-H | Asn 142 | ||||
| Lopinavir | −8.21 | 1.4318 | π-H | Asn 142 | |
| Favipiravir | −6.71 | 2.6054 | O N |
H-acceptor | His 163 |
| H-donnor | Phy 142 | ||||
| Hydroxychloroquine | −6.09 | 1.9408 | N | H-acceptor | Glu 166 |
| π-H | |||||
| Molnupiravir | −8.22 | 3.3472 | O | H-acceptor | Glu 166 |
| π-H | His 41 |
Besides, the binding affinity analysis of 2D projection protein-ligand complexes interactions are illustrated in Fig. 2 , it is noticed that all ligands all ligands form a bond with the receptor in Glu 166, among them nirmatrelvir and hydroxychloroquine which has represented two interactions. Ritonavir interacts with single bound π-H to Arg 279, lopinavir is bonded by the same bound type to Asn 142 residue. Remdesivir showed the higher number of bonds to the protein, H-donnor, H-acceptor and two π –H to Glu 166, His 163 and Asn 142 respectively. While favipiravir formed two bounds with His 163 and Phy 142.
Fig. 2.
2D visual representations of selected drug-Mpro complexes.
3.2. Multiple ligand simultaneous docking
Next, in the aim to explore the antiviral combination efficacy of the nirmatrelvir and ritonavir against Mpro protein, we checked the interactions of individual and multiple drug inside the receptor via the multiple ligand simultaneous docking. In the initial case, nirmatrelvir was optimized as the main drug in combination with other antiviral drugs (Fig. 3 ). Secondly, ritonavir was docked at first (Fig. 4 ).
Fig. 3.
3D view of the multiple molecular docking of the selected drugs with Mpro of SARS-CoV-2 (Omicron variant), nirmatrelvir is docked first. (a) Nirmatrelvir (cyano)/Ritonavir (orange), (b) Nirmatrelvir/Remdesivir (black), (c) Nirmatrelvir/Lopinavir (purple), (d) Nirmatrelvir/Favipiravir (blue) and (e) Nirmatrelvir/Hydroxychloroquine (green). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4.
3D view of the multiple molecular docking of the selected drugs with Mpro of SARS-CoV-2 (Omicron variant), ritonavir is docked first. (f) Ritonavir (orange)/Nirmatrelvir (cyano), (g) Ritonavir/Remdesivir (black), (h) Ritonavir/Lopinavir (purple), (i) Ritonavir/Favipiravir (blue) and (j) Ritonavir/Hydroxychloroquine (green). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Table 3, Table 4 displays the drugs docking results in the two case. In the single ligand docking, the binding affinities values indicate that nirmatrelvir showed an energy of −6.5 kJmol-1 and -7.5 kJmol-1 for ritanovir, while the results of multiple docking revealed that nirmatrelvir/ritonavir combined drugs produced the most synergistic effect, with a decreased binding energy of −7.0 kJmol-1 for nirmatrelvir and −7.6 for ritanovir compared with theirs single values and with the studied molecules. Nirmatrelvir/chloroquine presented a decreasing binding energy of −7.7 kJmol-1 chloroquine, but an increasing values for nirmatrelvir of −6.1 kJmol-1. In the other drugs combinations, no noteworthy changes were observed in comparison with individual docking energies values.
Table 3.
The obtained multiple docking results of studied drugs against Mpro of SARS-CoV-2 (Omicron variant).
| Drugs | Score (kJmol−1) |
|---|---|
| Nirmatrelvir/Ritonavir | −7.0/-7.6 |
| Nirmatrelvir/Remdesivir | −6.2/-7.7 |
| Nirmatrelvir/Lopinavir | −7.3/-7.5 |
| Nirmatrelvir/Favipiravir | −7.5/-5.6 |
| Nirmatrelvir/Chloroquine | −6.1/-7.7 |
| Ritonavir/Nirmatrelvir | −7.0/-7.6 |
| Ritonavir/Remdesivir | −6.8/-7.4 |
| Ritonavir/Lopinavir | −7.6/-8.4 |
| Ritonavir/Nirmatrelvir | −7.0/-7.6 |
| Ritonavir/Hydroxychloroquine | −7.2/-7.5 |
Table 4.
Summarized physicochemical proprieties and Lipinski's rule of studied drugs.
| MW (g/mol) | logp | H-bond acceptors | H-bond donors | TPSA (Å2) | Lipinski rule | |
|---|---|---|---|---|---|---|
| Nirmatrelvir | 499.53 | 2.385 | 8 | 3 | 131.40 | Yes; 0 violation |
| Ritonavir | 720.94 | 1.548 | 7 | 4 | 202.26 | no; 2 violations: |
| Remdesivir | 602.58 | 1.664 | 12 | 4 | 213.36 | no; 2 violations: MW > 500, |
| Lopinavir | 626.80 | 4.435 | 5 | 4 | 120.00 | Yes; 0 violation |
| Favipiravir | 157.10 | −0.934 | 4 | 2 | 88.48 | Yes; 0 violation |
| Hydroxyhloroquine | 319.87 | 4.511 | 3 | 1 | 31.39 | Yes; 0 violation |
Furthermore, with the aim of identifying the most two drugs gives an improved affinity to the target protein, we tested whether the combination of ritonavir with the rest of drugs. As shown in Table 2, both nirmatrelvir and ritonavir with −7.7 and −7.9 kJmol-1 exhibited the highest synergistic effect compared when tested alone −7.5/-6.5 kJmol-1 respectively. The other combinations did not produce any synergetic binding energy. The most noticeable antagonism effect was observed in the combination of ritonavir with remdesivir 6.8/-7.4 kJmol-1 compared with individual values 7.5/7.2 kJmol-1 respectively.
Table 2.
The obtained individual docking results of studied drugs against Mpro of SARS-CoV-2 (Omicron variant).
| Drug | Score (kJmol−1) |
|---|---|
| Nirmatrelvir | −6.6 |
| Ritonavir | −7.5 |
| Remdesivir | −7.2 |
| Lopinavir | −8.3 |
| Favipiravir | −5.3 |
| Hydroxychloroquine | −5.7 |
3.3. Physicochemical properties associated with Lipinski's rule
In order to investigate and determine which factors might correlate to the obtained synergistic effect in molecular multiple docking. For each of studied drugs, we first examined the physicochemical properties associated with Lipinski's Rule of Five (Table 4). The distribution coefficients (LogP) range between −0.934 for Favipiravir and 2.871 for hydroxychloroquine. Nirmatrelvir, ritonavir and remdesivir were showed close values 2.385, 1.548 and 1.664 respectively. Lopinair with 4.435 and hydroxychloroquine 4.511 were found to be higher than 3 (Optimal: 0 < LogP <3). Furthermore, another exception has been mentioned, the number of hydrogen bond acceptors and number of hydrogen bond donors was to be found convergent in Nirmatrelvir (8 H-acc, 3 H-don) and ritonavir (7 H-acc, 4 H-don). However, remdesivir, lopinavir, favipiravir and Hydroxyhloroquine presented a divergent values.
By analyzing of these previous results, we observed obviously that nirmatrelvir and ritonavir have close values of LogP and almost similarity in H-bond acceptors and H-bond donors, which might explain this important correlation between a synergetic action of these both drugs and their predicted physicochemical properties. In contrast, MW, TPSA and Lipinski rule exhibited heterogeneous values. The same for the bioavailability radar of the predicted physicochemical descriptors and pharmacokinetic properties displayed in Fig. 5 .
Fig. 5.
Bioavailability radar plot of studied drugs.
3.4. ADME evaluation
Additionally, we evaluated the synergistic drugs effect with their ADME (absorption, distribution, metabolism, and excretion) properties. As shown in Table 5 , the calculated pharmacokinetic parameters did not appear any significant correlation with the synergetic action of the studied compounds.
Table 5.
Predicted pharmacokinetic parameters of studied drugs.
| Drugs |
SuissADME |
pkCSM |
||||
|---|---|---|---|---|---|---|
| BBB | Skin Permeability (cm/s) | G I | Water solubility log mol/L) | Caco2permeabilty (log Papp in 10–6 cm/s) | Intestinal absorption (human) (% Absorbed) | |
| Nirmatrelvir | No | −7.81 | High | −4.013 | 0.155 | 65.723 |
| Ritonavir | No | −6.40 | Low | −3.358 | 0.377 | 69.45 |
| Lopinavir | No | −5.93 | High | −4.819 | 0.063 | 65.607 |
| Remdesivir | No | −8.62 | Low | −3.07 | 0.635 | 71.109 |
| Favipiravir | No | −7.66 | High | −2.121 | 0.623 | 91.69 |
| Hydroxychloroquine | No | −4.96 | High | 1.624 | 89.95 | −2.679 |
3.5. Structural comparison
Next, according to the visual inspection of the 2D and 3D structure of six ligands, as illustrated in Fig. 6 , the common feature between these molecules can be observed in the presence of amid group in nirmatrelvir and ritonavir. This functional group plays a key role in the water solubilization properties and many clinically approved drugs. On the other hand, ritonavir, remdesivir and lopinavir structures contain a highly conjugated π-bond system with aromatic rings.
Fig. 6.
2 D and 3D visual representation of studied drugs.
3.6. Global reactivity descriptors parameters
In order to evaluate the potential combinations of selected drugs, the global chemical reactivity descriptors were investigated, these quantum chemical parameters act as mediators to understand the kinetic stability and chemical reactivity of the molecule [27]. Otherwise, they are used in the development of structure-property (QSPR), quantitative structure-activity relationships (QSAR) and structure-toxicity (QSTR) [28]. The contours of HOMO and LUMO orbitals for the studied drugs are illustrated in Fig. 7 and their energy EHOMO and ELUMO values are summarized in Table 6 .
Fig. 7.
Illustrate the energy gap and distribution of HOMO and LUMO of each studied ligand.
Table 6.
The calculated HOMO, LUMO energies of investigated drugs and their corresponding global reactivity descriptors by using B3LYP/6-31G(d) level of theory.
| Nirmatrelvir | Ritonavir | Remdesivir | Lopinavir | Favipiravir | Hydroxychlorquine | |
|---|---|---|---|---|---|---|
| E (au) | −1769.42 | −1769.899 | −2321.56 | −2034.01 | −607.27 | −607.46 |
| Dipole moment (D) | 3.91 | 4.41 | 10.21 | 4.25 | 5.69 | 5.28 |
| EHOMO (eV) | −0.2472 | −0.2473 | −0.2069 | −0.2168 | −0.2438 | −0.2340 |
| ELUMO (eV) | −0.0404 | -O.O373 | −0.0291 | −0.0024 | −0.0837 | −0.0749 |
| ΔE Gap (eV) | 0.2069 | 0.2099 | 0.1877 | 0.21664 | 0.1600 | 0.1591 |
| I (eV) | 0.2472 | 0.2473 | 0.2069 | 0.2168 | 0.2438 | 0.2340 |
| A (eV) | 0.0404 | O.O373 | 0.0291 | 0.00242 | 0.0837 | 0.0749 |
| χ (eV) | 0.1438 | 0.14231 | 0.1180 | 0.1096 | 0.1637 | 0.1544 |
| μ (eV) | −0.1438 | −0.1423 | −0.1180 | −0.1096 | −0.1637 | −0.1544 |
| ɳ (eV) | 0.1034 | 0.1049 | 0.0889 | 0.1072 | 0.0800 | 0.0795 |
| S (eV) | 4.8355 | 4.5454 | 5.5928 | 4.6641 | 6.25 | 6.24 |
Based on the computation of the HOMO and LUMO energy of the optimized selected drugs, we can calculate the following descriptors; the energy gap; the energy gap (ΔE = ELUMO-EHOMO), Ionization potential; (I = EHOMO), electron affinity; (A = ELUMO), electronegativity (χ = -½ (EHOMO + ELUMO)), electronic chemical potential (μ = ½ (EHOMO + ELUMO) = -χ), global chemical hardness (η = ½ (ELUMO—EHOMO)) and global softness (s = 1/2η) [29]. The mentioned note that should be indicate from the global minimum energies values, Nirmatrelvir with −1769.42 a.u and Ritonavir with −1769.899 a.u appeared almost similar values. Favipiravir and hydroxychloroquine revealed also close results. The DFT-calculated data indicate that the dipole moment of these six drugs was in the order of nirmatrelvir 3.91< lopinavir 4.25 < ritonavir <4.41 < hydroxychlorquine 5.28 < favipiravir 5.69 < remdesivir 10.21. The highest dipole moment of nirmatrelvir and ritonavir signified theirs strong intermolecular interactions. Moreover, the frontier molecular orbitals (FMOs) theory often plays a dominant roles in the understanding of organic reactions mechanisms, and they are also pertinent in the analysis of drug-receptor interactions. These most important orbitals in a molecule are the frontier molecular orbitals, Highest Occupied Molecular Orbital, refers to the ability to donor an electron to an acceptor; and Lowest Unoccupied Molecular Orbital, refers to the ability to accept an electron of the molecule. Energy difference between HOMO and LUMO orbital, called energy gap become increasingly important sign to investigate the stability structure of molecules. It has been noticed that the energy value of the uppermost filled orbital of compounds was −0.2472 ev, −0.2438 ev, −0.2473 ev, −0.2340 ev, −0.2168 ev and −0.2069 ev for nirmatrelvir, ritonavir, favipiravir, chloroquine, lopinavir and remdesivir respectively. The order of ELUMO can be arranged in the order, lopinavir −0.0024 ev > remdesivir −0.0291 ev > ritonavir −0.0373 ev > nirmatrelvir −0.0404 ev > hydroxychlorquine −0.0749 ev > favipiravir −0.0837 ev. The calculated HOMO-LUMO energy gaps are in the range narrow range of 0.1591–0.2069 ev, these results indicate that hydroxychloroquine was harder than the other compounds. Nirmatrelvir and ritonavir exhibited values of 0.2069 and 0.2099 ev respectively. For the rest of compounds, the values were as follows: remdesivir 0.1877, ev lopinavir 0.2166 ev, favipiravir 0.1600 ev and hydroxyhloroquine 0.1591 ev. Similarly, the other chemical reactivity descriptors, such as electronegativity (c), global hardness (h), softness (d) also elucidated a quite close values for the both Nirmatrelvir/Ritonavir ligands.
According to these obtained global reactivity descriptors results, and after comparing each two drugs values, nirmatrelvir and ritonavir with insignificant difference, appeared to be closer in all computed parameters. These findings were in agreement with the binding affinity of multiple docking studies, suggesting that potent synergetic effect produced when we combine nirmatrelvir with ritonavir ligand.
4. Conclusion
A computational approach was used to confirm the performance of the recent medication Paxlovid. The potential combination of nirmatrelvir/ritonavir against Mpro omicron variant was inspected brought into comparison with five antiviral drugs. After that, the individual efficacy of drugs was evaluated, after that, every both of them were computed in multiple molecular docking. Ritonavir exhibited the strongest binding infinities in the individual evaluation. The multiple docking results demonstrate a strong synergetic effect between combined nirmatrelvir and ritonavir drugs. After performance analysis, when we compare the investigated parameters values for each two compounds, the correlation between the physicochemical properties and synergetic drugs effect, indicate a close values of logP, H-bond acceptors, and H-bond donors of nirmatrelvir and ritonavir. In contrast, pharmacokinetic parameters did not appear any significant relationship with the synergetic potential of selected association compounds. The comparison of density functional theory calculations suggests a similarity of global descriptors with insignificant difference for nirmatrelvir and ritonavir drugs. These theoretical informations confirm the efficiency of ritonavir-boosted nirmatrelvir ‘Paxlovid’ drug as novel antiviral treatment in reducing the risk of death mortality or hospitalization of covid-19 patients.
Declaration of competing interest
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.
Acknowledgments
The authors would like to thank the Journal of the Indian Chemical Society for supporting this work.
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