key: cord-0838879-ije5rjrv
authors: Kumari, Kamlesh; Kumar, Ajay; Singh, Prashant; Kaushik, Nagendra Kumar
title: In silico study of remdesivir with and without ionic liquids having different cations using DFT calculations and molecular docking
date: 2022-01-02
journal: Journal of the Indian Chemical Society
DOI: 10.1016/j.jics.2021.100328
sha: 08a5c5b278a97f49c291dbd76b0b0f20f568e2b7
doc_id: 838879
cord_uid: ije5rjrv

The new coronavirus is trying the kill the humanity with its infectious nature and its first infection was reported in 2019; named as COVID-19. Health-care systems are using repurposing drugs to cure the patients from this infection. Remdesivir found to have good potential against the infection and is being extensively used during the 1st and 2nd wave of COVID-19. Therefore, in the present work, authors have studied the interaction of remdesivir with different ionic liquids with change in cations using density functional theory calculation in gaseous and water. Based on the DFT calculations, it was found that remdesivir interacts with different ionic liquids effectively based on the energy; further, the change in free energy for Remdesivir-[Bet-ester][Lev] was found to be satisfactory as −3223.5758 and −3223.6533 hartree per particle in default and water respectively but more than Remdesivir-[Chol][Lev]. Further, the potential of remdesivir with and without ionic liquids against the main protease of SARS-CoV-2 was investigated using molecular docking. Results revealed that Remdesivir-[Chol][Lev] and Remdesivir-[Chol-ester][Lev] have shown the promising results with binding energy of −129.64 kcal/mol and −125.44 kcal/mol respectively. It is important to mention that changing the cations in ionic liquid play an important role in the docking. It is also observed that the ionic liquid having sodium as cation then the binding energy against Mpro of CoV is poor and even less than the remdesivir alone.

The world has faced the threat of the several viral attacks in past and reported that they have taken the lives of millions. The recent new coronavirus attack has endangered humanity and is often referred to as COVID-19 by World Health Organization. A continuous fever, chestpain, cough, pneumonitis patches in lungs causes difficulty in breathing are some of the common symptoms of the infection due to new coronavirus. [1] [2] [3] [4] The intensity and progress of this disease can be correlated with host immunological dysregulation. The advancement of novel antiviral drugs should be economically expansive and time taking against the new coronavirus and virus after the mutation of viruses in due course of time, that ultimately reduce the efficiency of medications partially or completely. [5] [6] [7] [8] The world has faced the 1 st and 2 nd wave of infection due to coronavirus and start experiencing the 3 rd wave due to mutation in coronavirus. It has also reported that OMICRON, a new mutated coronavirus may infect the vaccinated people. In the previous two waves, repurposing drugs were used to cure the symptoms of the infection and could be synthesized in huge quantity, a potential alternative candidate to deal with this situation.

Repurposing drugs are of considerable importance in curing the infection from SARS-CoV-2.

Remdesivir has been used in the treatment of various viral infections like Ebola Virus, severe acute respiratory syndrome (SARS), Marburg Marburg virus, Middle East respiratory syndrome (MERS) and others. Drug repurposing reduces the cost in less time. It involves repurposing of antivirals to inhibit the protease activity and inhibit the RNA synthesis of the virus. [9] [10] [11] Remdesivir restrict reverse transcription and has potential promising inhibition for SARS-CoV-2. Remdesivir was extensively used in many countries during the second wave of infection due to new coronavirus. [7, [12] [13] [14] [15] There is need to investigate the electronic structure of remdesivir and can be done by density functional theory (DFT) calculations using various computational tools. [16] [17] [18] [19] [20] Electronic structures of the compounds can be investigated in different solvents and different temperatures. It provides the enthalpy, free energy, solubility, different spectral studies to know about the structural and electronic behaviour of the compounds. [21] [22] [23] [24] Ionic liquids (ILs) are highly demanded chemical entities by the academic institutions and industries as they cause cost-effective, easy to synthesize, reused and have the ability to increase the activity of biological potential molecules. [25] [26] [27] [28] [29] They are explored for the protein stabilization, solubilize biomolecules and chemical entities, catalysis, conducting, enzyme extraction and others. Researchers are using working on the use of repurposing drugs against the symptoms of the new coronavirus infection, therefore remdesivir played J o u r n a l P r e -p r o o f promising role. [30] Further, it is reported that the synergistic effect of drugs showed better results than the individual one. Therefore, there is a need to understand the impact of ionic liquids on the structural and biological potential of remdesivir. [31] Research have explored the interaction of ionic liquids with small molecules using DFT calculations and investigate the impact of ionic liquids on the potential of small molecules for the inhibition of proteases.

Even, ILs can be used as a potential antiviral agent against the main protease of SARS-CoV-2. Further, impact of ILs on the acyclovir/ ganciclovir against the Mpro of nCoV is studied using molecules docking. [30, 32] In the present work, authors have focused on the investigation of thermodynamic stability of remdesivir with and without various ionic liquids (ILs) having different cations using Gaussian 16. Further, a synergistic effect of the remdesivir with different ILs against the main protease (Mpro) of new coronavirus (nCoV) has been investigated using molecular docking.

Authors have designed remdesivir and its combination with four ionic liquids were drawn on chemdraw as in Table 1 to investigate their stability as well as the synergistic effect against the main protease of SARS-CoV-2. [33] 

Various thermodynamics parameters (zero-point energy, thermal energy, thermal enthalpy and thermal free energy) of the 1-5 were determined using DFT calculations as in (Table 2) .

Further, the optimization energy and dipole moment of 1-5 were also determined to J o u r n a l P r e -p r o o f understand the arrangement of atoms and solubility in water. Dipole moment of any system or molecule may be used to understand the polar character. If a molecular has high dipole moment indicate more polarity or difference in charge density; therefore, will be soluble in water. These data are used to understand the interaction of remdesivir with and without various ionic liquids having different cations in gaseous state and water. It tells about the variation of the stability of remdesivir in the presence of ionic liquids with different cations. Further, the energies of frontier molecular orbitals (HOMO and LUMO) were determined as in Table 3 . 

Simulated infrared spectra of 1-5 in gaseous and water are plotted to understand different types of stretching as in 

Molecular docking is an important approach to study the interaction of small molecules with the different receptors of interest using computational tools like iGemdock. [42] It gives binding energy for the formation of complex between the drug and target due to different interactions. [43, 44] Remdesivir (5) with and without ionic liquids (1-4) were docked against Mpro of nCoV. In this work, PDB-6LU7 for main protease of SARS-CoV-2 has been downloaded from RCSB data bank and was prepared using the chimera before docking as in our previous work. [16, 17] Then, 1-5 were docked against the main protease of SARS-CoV-2 using the iGemdock, a computational tool as in Table 4 . , that is, 2 with the amino-acids of main protease of SARS-CoV-2 has been studied based on the binding energy in Figure 3 . -CH stretching of aldehyde (2500-3000 cm -1 )

For 1 in gaseous state, single peak appeared at 2900 cm -1 while in water, peak is shifted at 2950 cm -1 . For 2 in gaseous state, no stretching is seen while in water, an intense peak is observed at 2890 cm -1 . For 3 in gaseous state, an intense peak is observed at 2840 cm -1 while in Water, stretching is shifted to 2800 cm -1 . For 4 in gaseous state, peak is observed at 2500 cm -1 while in water, peak is shifted to 2910 cm -1 .

For 1-5 in gaseous state and water, a strong and intense peak is observed in the range of 1650-1710 cm -1 .

For 1-5 (gaseous and water), peaks for C-H bending were observed in the range of 1300-1500 cm -1 ; a strong and one weak peak of P=O stretching also recorded in 1130-1295 cm -1 .

-C=C-bending of mono substituted and di-substituted alkene (500-1000 cm -1 )

Various peaks of -C=C-bending for 1-5 in gaseous state and water are appeared in the range of 500-1000 cm -1 .

The 3 showed the promising potential with binding energy of -125.446 kcal/mol. On using sodium as cation in ionic liquid, the obtained binding energy is less than for remdesivir alone.

While the binding energy for the formation of complex is better in presence of ionic liquids.

Funding: (information that explains whether and by whom the research was supported)

DFT calculations were performed at SCFBio, Indian Institute of Technology, Delhi and the authors are thankful to Professor B. Jayaram to access the facilities available and training.

"I, Prashant Singh (Corresponding Author), declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere. I further confirm that the order of authors listed in the manuscript has been approved by all of us. There is also no potential conflict of interest.

The data is available and will be made available to the journal or any reader on reasonable request.

Code availability: (software application or custom code) N/A J o u r n a l P r e -p r o o f

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