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| ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 6
| Issue : 4 | Page : 510-514 |
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Modified intelligent magnetic nanoparticles as a treatment for severe acute respiratory syndrome coronavirus type 2 In Silico
Arefeh Khodaee1, Nima Shirmohammadi1, Reza Aghanouri2
1 Department of Scientific Research, Kian Asa Center for Preventive Medicine (None Governmental Center Licensed by the Ministry of Health and Medical Education of Iran), Tehran, Iran
2 Scientific Authority Center for Countering Biological Threats, Tehran, Iran
| Date of Submission | 16-Aug-2022 |
| Date of Acceptance | 01-Nov-2022 |
| Date of Web Publication | 15-Dec-2022 |
Correspondence Address:
Reza Aghanouri
Scientific Authority Center for Countering Biological Threats, Tehran
Iran
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/bbrj.bbrj_266_22
Background: The pandemic situation of the new coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-COV-2]) forces drug designers to formulate a new intelligent drug for this disease effective to treat all mutations of the virus. One way to control all mutations of virus is inhibition of spike protein (binding with angiotensin-converting enzyme 2 [ACE-2]) duo to inhibit the viral entry. Viral entry is the first step for virus to start infection. Methods: In this work, the interactions of SARS-COV-2 spike protein and ACE-2 are evaluated in silico by docking process and four different ligands are estimated to simulate those interactions to avoid bindings with ACE-2 needed for viral entry in reality. All ligand–receptor interactions are considered. Results: Results approve the suggested ligands in this work, have a definite inhibitory effect on SARS-COV-2 spike protein based on the interactions which they make with the receptor-binding domain. Docking process is done repeatedly to assure conclusions. Conclusion: All interactions were considered by docking of the receptor and ligands. All kinds of interactions contain Hydrogen bonds, steric bonds and etc approving the possibility of ligands to bind the receptor. These interactions approve the antiviral effects of ligands. As the result, ligands were approved to have an antiviral effect on SARS -COV -2. ligands 1 and 2 have higher affinity than other ligands which is completely compatible with the results invitro done by this paper authors.
Keywords: Docking, ligand, nanoparticles, protein, receptor, virus
How to cite this article:
Khodaee A, Shirmohammadi N, Aghanouri R. Modified intelligent magnetic nanoparticles as a treatment for severe acute respiratory syndrome coronavirus type 2 In Silico. Biomed Biotechnol Res J 2022;6:510-4 |
How to cite this URL:
Khodaee A, Shirmohammadi N, Aghanouri R. Modified intelligent magnetic nanoparticles as a treatment for severe acute respiratory syndrome coronavirus type 2 In Silico. Biomed Biotechnol Res J [serial online] 2022 [cited 2023 Apr 1];6:510-4. Available from: https://www.bmbtrj.org/text.asp?2022/6/4/510/363577 |
| Introduction | |  |
In biology and other experimental sciences, an in silico experiment is one performed on a computer or through computer simulation. The phrase is pseudo-Latin for “in silicon” (in Latin it would be in silicio), referring to silicon in computer chips. Actually in silico study helps us to estimate the effectiveness of hypothesizes before doing any animal and clinical trials, so it can reduce the risk of animals and people death.[1] By estimating the bond energies, scientists can assure the possibility of protein–ligand interactions and drug activity. As an example, this technique could be utilized to study the antiviral effects of candidate drugs to cure coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). COVID-19 is an infectious disease caused by a novel SARS-CoV-2 pandemic which initially started in Wuhan province in China and has now affected >200 countries worldwide and declared a pandemic.[2],[3],[4] As per the statistics available, mortality is high in older age group individuals (>60 years of age) and people with other morbid conditions. In addition to acute respiratory distress syndrome and respiratory failure, COVID-19 is now known to manifest as systemic inflammation, leading to sepsis, acute cardiac injury, heart failure, and multiorgan dysfunction in patients at high risk.[3] Metal oxide nanoparticles with their novel properties have had increasing interest for these kinds of biomedical applications. In recent years, monodispersed superparamagnetic iron oxide nanoparticles were developed for various biological applications such as antiviral activity, drug delivery, protein purification, magnetic resonance imaging, and hyperthermia treatment.[5],[6] Magnetic nanoparticles with a size range of <1000 nm have been used to treat proteins (5–50 nm), genes (10–100 nm), viruses (20–450 nm), and cells (10–100 mm) without any difficulty. The advantages associated with superparamagnetic nanoparticles are easy preparation, active surface functionality, chemical stability, fast response under an external magnetic field, low toxicity, and cost-effectiveness. However, it is difficult to use pure Fe3O4 nanoparticles for these applications due to their high surface-to-volume ratio and strong dipole–dipole interaction between the particles and agglomeration.[7] All these problems were solved by encapsulating the iron oxide nanoparticles in surface active agents. The encapsulation provides improved chemical, mechanical, solubility, and biological stability to the environment, so based on this information, modified magnetic nanoparticles were used as a treatment for COVID-19 in this work. In the first step, the interactions (ligand–receptor = drug–target protein) were confirmed with aid of in silco assay.[8] The in silico assay results are described in this article in detail. Not any available ligand structure in databanks was used to design the drug, and all information about suggested drug are noble.
| Methods and Material | | |
Proteins
Macromolecules, especially proteins are mostly the targets of bindings with other molecules. It is important to know how a special molecule would make a complex with proteins. To assure these protein–drug bindings, the procedure was followed:
Selection of protein
Crystal structure of the SARS-COV-2 spike protein receptor-binding domain (RBD) bound with angiotensin-converting enzyme 2 (ACE2) (protein data bank [PDB] ID = 6M0J) was selected from PDB to estimate ligand–receptor bindings.[9]
Separation of target protein
Discover Studio version (4.2) was used to separate RBD of spike protein from mentioned crystal structure by neglecting ACE2 receptor and water molecules.
Optimization of protein
We optimized the separated structure by Molecular Operating Environment (MOE) molecular viewer 2013. A quick receptor optimization was used and probable defects were discovered and amino acids were localized on active sites of this protein by stereochemical estimations. Finally, the last structure was the most stable conformer with least energy level.[10] The results of optimization (physicochemical properties, changes in physiological environments, and effects of different parameters) are described in conclusions with details.
Estimation of interactions with water molecules
The interactions were studied again to assure optimization in the presence of water molecules. It helped to have more detailed information about estimated ligand–receptor interactions.
Finding the active sites
The active sites of optimized structures were found by MOE virtual Docker 2013 by analyzing the amino acid sequences as a result of the site finder item in MOE application.
Ligand
Ligand is any kind of molecule which can have certain interactions with receptor. In this work, the receptor is the optimized structure of SARS-COV-2 spike protein RBD and ligand is modified magnetic nanoparticles (Fe3O4).
Two-dimensional structure of the ligand
First, a cluster of Fe3O4 magnetic nanoparticles was drawn in two-dimensional (2D) ChemDraw professional 16. In the next step, the cluster was modified in four different methods to consider the best candidate for the final structure based on stereochemical parameters.
Three-dimensional design
After drawing a 2D structure of estimated ligand, the structure was optimized by Chem three-dimensional (3D) 16 to have optimized the 3D structure of the ligands.
Complete optimization
The 3D structure was optimized completely by the Gaussian version (09). The application optimized the structure based on Hückel's principle and molecular dynamics.
Molecular docking
Molecular docking simulates the ligand–receptor interactions. It is the most important procedure which helps to assure all estimations are reliable. The docking was repeated several times to prove results are not affected by random. AutoDock 4.2, MOE 2019, and Molegro Virtual Docker 2013 were used to do the dock. The optimized structure of SARS-COV-2 spike protein RBD unit was selected as receptor, and the candidate drug was selected as a ligand and all interactions were considered.[11]
| Result and Discussion | | |
Structures and properties of ligands
In the first step, ligands were designed in four different structures. You can see the ligands in detail in [Figure 1]: different bond (stretch, bend, and total) energies of four ligands were calculated to compare the stability of ligands by MOE Molecular Viewer 2013 and choosing the nest ligand to bond with the target. Results are shown in [Table 1].
Physicochemical properties of ligands
The physicochemical properties (pKa, Log S, and Log P) of ligands were calculated by ALOGPS online server to assume solubility, stability, and other properties of ligands which help to have a better selection among four created ligands. The results are shown in [Table 2].
Selection of protein
The structure of SARS-CoV-2 RBD bound to ACE2 with PDB ID of 6M0J was selected to estimate the ligand–protein interactions by separation of the structure of SARS-COV-2 spike protein and ACE2 RBD. You can see the structure in [Figure 2] and the structure exists in PDB website. More explanations about the structure could be found on the mentioned website too.[12] | Figure 2: Overall structure of SARS-CoV-2 RBD bound to ACE2 (6M0J)[12] ACE2 is shown in green. The SARS-CoV-2 RBD core is shown in cyan and RBM in red. Disulfide bonds in the SARS-CoV-2 RBD are shown as sticks and indicated by arrows. The N-terminal helix of ACE2 responsible for binding is labeled
Click here to view |
The structure of SARS-CoV-2 spike protein in the prefusion state (flexibility analysis, 1-up open conformation) (PDB ID = 6ZP7) is shown in [Figure 3] to complete information. This structure was used as receptor for docking with ligands to consider interactions. | Figure 3: The structure of SARS-CoV-2 spike protein in prefusion state (flexibility analysis, 1-up open conformation) (PDB ID = 6ZP7)
Click here to view |
Ligand–receptor interactions
Finally, all interactions were considered by docking the receptor and ligands. All kinds of interactions contain hydrogen bonds, steric bonds, etc., approving the possibility of ligands to bind the receptor. These interactions approve the antiviral effects of ligands as shown in [Figure 4], [Figure 5], [Figure 6], [Figure 7]:
Information about ligand–protein bond energies (hydrogen bonds – steric bonds – total energies) and affinity of ligand to protein as the receptor is summarized in [Table 3]. This information approves the antiviral effects of ligands. Totally docking, as a method to estimate possible ligand–receptor interactions, was done by different applications such as AutoDock 4.2, MOE 2019, Molegro Virtual Docker 2013, and online servers to approve designed ligands have antiviral effect by making interactions with SARS-COV-2 spike glycoprotein and interfering viral entry.
| Conclusion | | |
As the result, ligands were approved to have antiviral effects on SARS-COV-2. These results were obtained by ligand energy inspector in Molegro 2013. It shows ligandS 1 and 2 have higher affinity than other ligands which is completely compatible with results in vitro done by this article's authors.[13]
Limitation of study
The study in vivo and vitro may be different that has to be investigated
Acknowledgment
The authors would like to thank Dr. Maryam Rahimi, Marzieh Vanayi, Zahra Farahani, Mohammad Javad Hallaji, and Dr. Reza Gheshlaghi for their cooperation in carrying out the project and the University of Malayer for their help, Garsha Pajooh ScientificBased Company and Kian Asa Pars Center for Preventive Medicine and Health Promotion have provided financial support for the project.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3]
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