Molecular Interactions of Fullerene-Based Derivatives and SARS-CoV-2

doi:10.21203/rs.3.rs-40770/v1

Download PDF

Research Article

Molecular Interactions of Fullerene-Based Derivatives and SARS-CoV-2

https://doi.org/10.21203/rs.3.rs-40770/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

There are no expedient proven to stop the outbreak of SARS-CoV-2 at this phase. This leads to diversity of endeavors to find out the effective drug or vaccine. One of these possibilities is to exploit the unique characteristics of fullerene-based derivatives. A computer-aided method (molecular docking) was applied to assess the differential binding behavior of these compounds and determining hydrophobic forces, electrostatic interactions, and hydrogen bonds played vital roles in the interactions with SARS-CoV-2 spike protein. The molecular docking calculation clarifies the binding mode and the binding sites may facilitate the development of new or improved therapeutic regimes effective against COVID-19. Fulleropyrrolidine-NH2 seems to be promising candidate for interacting with SARS-CoV-2 binding site.

Biophysics

Fulleropyrrolidines

Receptor-binding domain

COVID-2019

Molecular docking

RNA viruses are world-wide pathogens as a consequence of their ability to evolve rapidly and adapt to new environments. Of those, positive-stranded RNA corona viruses are a large family of pathogens that usually cause mild to moderate upper-respiratory tract illnesses, like the common cold [1]. However, three new corona viruses have originated from animal reservoirs over the past two decades to cause serious and widespread illness and death [2-4].

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of Betacoronavirus genus [5, 6]. The spherical morphology of SARS-CoV-2 is composed of four main structural proteins including spike, envelope, membrane and nucleocapsid proteins that play an important role in viral synthesis and replication [7]. The viral spike (S) glycoprotein is present on the viral surface as a homo-trimer [8]. The S-protein is composed of two subunits: S1 and S2, mediating attachment and membrane fusion, respectively [9]. The receptor-binding domain (RBD) of S1 subunit is the main component of the virus that induces neutralizing antibodies against the virus and is thus considered potential targets for development of drugs and vaccines for SARS-CoV-2 [10,11]. SARS-CoV-2 and SARS-CoV strains engage the same receptor angiotensin-converting enzyme 2 (ACE2) in humans to facilitate viral entry into target cells [11-15].

Fullerene is an allotrope carbon nanostructure with a monodisperse size and morphology. Fullerene nanoparticles have received a considerable amount of attention owing to their unique physical and chemical properties. Moreover, fullerene-based nanomaterials has very wide array of applications in the field of biomedicine. Water-soluble fullerene compounds have inhibitory effects against human immunodeficiency virus (HIV) proteases, influenza A viral infection, and HCV [16-20]. Virus-induced redox imbalance is a major cause of change the intracellular redox state [21-23]. However, the most prominent fullerene properties are its reactive oxygen species scavenging [24] while the antioxidant effect of fullerene derivatives depends on their chemical structure [20].

Among different routes of molecular modeling computational biophysics is one of the most important approaches that can be used to find out an effective treatment for such pandemics. Therefore, this study has been undertaken to study the molecular interaction of fullerene-based derivatives with receptor-binding domain (RBD) of SARS-CoV-2 spike through docking experimentation in order to understand the underlining mechanisms to be used in designing more effective drugs for SARS-CoV-2 infection.

Initially, the molecular models of the six Fulleropyrrolidine-1-carbodithioic acid 2; 3 and 4-substituted-benzyl esters-based derivatives at ortho, meta and para positions respectively presented in this study were previously built with the use of Gauss View [25] software. These compounds have been previously reported having antiviral activity [26-28]. Chemical structures of the derivatives were provided in figure 1. Then, the geometry of the compounds was optimized in the vacuum by performing PM6 semiempirical quantum mechanical level of theory as previously reported [29, 30].

Two different molecular docking protocols were used for predicting the binding affinities for fullerene derivatives. The co-crystallized structure of SARS-CoV-2 spike receptor binding domain in complex with Angiotensin-Converting Enzyme 2 (ACE2) (PDB 6m0j) [31] was downloaded from the protein data bank and prepared for docking using UCSF Chimera-1.14 [32]. Briefly, the receptor binding domain (RBD) was extracted from ACE2, and the N-acetyl glucosamine moieties were removed from the structure. The polar hydrogen atoms were added to the protein, and gasteiger charges were added to each atom and the non-polar hydrogen atoms were merged to the protein structure employing Autodock Tools 1.5.6 [33]. The structure was then saved in PDBQT file format for docking studies in Autodock Vina 1.1.2 software [34]. Autodock vina is employed for its ability to find bioactive conformations with a very good level of accuracy and it was also found to retain a notable efficiency as the number of rotatable bonds increased. DINC 2.0 web server [35] is applied as well. DINC is a parallelized meta-docking method for the incremental docking of large ligands. The strategy of DINC involves incrementally docking overlapping fragments with a growing number of atoms, while maintaining the number of flexible bonds constant during this incremental process. First, the spatial coordinates of ACE2 were used as a reference in determining the binding site and the docking grid box. The grid size was set to ~ 36 Å× 50 Å× 21 Å xyz points with grid spacing of 0.375 Å and grid center was designated at dimensions (x, y, and z): -30.0, 29.0 and 6.75. Such approach may give the best result for estimation of the binding between protein and ligand [36].

It is interesting that these two docking protocols reveal the possibility of fulleropyrrolidine-based molecules interaction with the binding site of SARS-CoV-2 spike protein. All the generated complexes in DINC 2.0 server and Autodock vina were ranked on the bases of energy associated with the protein-ligand interactions. Top ranked binding energies (kcal/mol) in the DINC 2.0 server output files were taken as a response in each run. The obtained docking results exhibited relatively high potential for binding of fulleropyrrolidine compounds in terms of effective molecular interaction with the investigated protein, SARS-CoV-2 spike RBD. The relative binding affinities between the ligands containing CN and NH2 groups have exhibited better binding affinity compared to the rest of compounds.

Table 1: Calculated binding affinity as kcal/mol for binding of fulleropyrrolidine derivatives, meta-Me and meta-Cl, ortho-CN and ortho-COMe, para-NH₂ and para-NHCH3 with SARS-CoV-2 via two molecular docking protocols named Autodock Vina 1.1.2 software and DINC 2.0 web server.

Structure	DINC2 web server Binding affinity (kcal/mol)	Autodock vina Binding affinity (kcal/mol)
Meta-Me-COVID-19	-7.8	-8.1
Meta-Cl-COVID-19	-8.2	-8.0
Ortho-CN-COVID-19	-8.4	-8.3
Ortho-COMe-COVID-19	-7.9	-7.8
Para-NH₂-COVID-19	-8.3	-7.9
Para-NHCH3-COVID-19	-7.80	-7.9

Ligand binding stability was then assessed by monitoring the residue contribution to protein-ligand interactions. The docked complexes are analyzed by the protein–ligand interaction profiler (PLIP) server [37] to classify the types of interactions between the fulleropyrrolidine molecules and individual amino acids within the spike RBD binding site. The fulleropyrrolidine-based molecules were surrounded in spike RBD binding site by hydrophobic residues such as Val407, Asn437, Val503, Tyr505, and Tyr508. Moreover, four ligands stabilized further through π-cation interactions with two residues Lys378 and Arg408. However, in para-NH₂ molecule, we do find significant preference for π-π stacking with Tyr449 and Tyr505 residues. It could be inferred that the hydrophobic interactions play crucial role in stabilizing of the protein-ligand complex. Also, a hydrogen bond was observed between the NH₂ group and Tyr505 amino acid residue.

The spike protein–receptor interaction is the primary determinant for a coronavirus to infect a host species and also governs the tissue tropism of the virus [38]. On the other hand, the zinc metallopeptidase ACE2 has been identified as the main entrance (receptor) for coronavirus into the cells [39].

The cornerstone for combating the SARS-CoV-2019 pandemic is to construct inhibitors that prevent the association of both the virus and its host’s receptor. No specific treatments for SARS-CoV-2019 exist right now. However, many studies call for exploiting the possibilities of nanomaterials.

The fullerene-based nanoparticle compounds could be considered for its antiviral potential and could be a valuable source for the design and development of new anti-infective compounds. To achieve this purpose, we explore five fullerene-based formulations to bind the receptor-binding domain of spike protein. It is interesting that fulleropyrrolidine derivatives have the potentialities to bind the RBD. However, the RBD structural change associating the binding of nanoparticle is awaiting further investigations.

Funding:

This research received no external funding

Conflicts of interest

The authors declare that they have no conflict of interest. The manuscript has been read and approved by all of the authors.

[1] Denison MR (2008) Seeking membranes: positive-Strand RNA virus replication complexes. PLoS Biol 6(10): e270.

[2] Amer HM (2018). Bovine-like coronaviruses in domestic and wild ruminants. Anim Health Res Rev 19: 113–124.

[3] Cui J, Li F, Shi ZL (2019). Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 17: 181-192.

[4] Guarner J (2020). Three emerging coronaviruses in two decades. Am J Clin Pathol. 153: 420-421.

[5] Gorbalenya, A.E., Baker, S.C., Baric, R.S. et al (2020). The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 5: 536–544. https://doi.org/10.1038/s41564-020-0695-z

[6] Ashour HM, Elkhatib WF, Rahman MM, Elshabrawy HA (2020). Insights into the recent 2019 novel coronavirus (SARS-CoV-2) in light of past human coronavirus outbreaks. Pathogens 9(3): 186. doi:10.3390/pathogens9030186

[7] Zheng J (2020). SARS-CoV-2: an emerging coronavirus that causes a global threat. Int J Biol Sci 16(10): 1678-1685.

[8] Song W, Gui M, Wang X, Xiang Y (2018). Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog 14(8): e1007236.

[9] Spann W, Cavanagh D, Horzineck MC (1988). Coronaviruses: structure and genome expression. J. Gen. Virol. 69: 2939-2952.

[10] Okba, N., Müller, M. A., Li, W., Wang, C., GeurtsvanKessel, C. H., Corman, V. M....Haagmans, B. L. (2020). Severe acute respiratory syndrome coronavirus 2−specific antibody responses in coronavirus disease patients. Emerging Infectious Diseases 26(7), 1478-1488.

[11] Tai W, He L, Zhang X. et al (2020). Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol 17: 613–620.

[12] Li F, Li W, Farzan M and Harrison SC (2005). Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 309: 1864–1868.

[13] Li W, Moore M, Vasilieva N et al (2003). Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 426: 450–454.

[14] Shang J, Ye G, Shi K et al (2020). Structural basis of receptor recognition by SARS-CoV-2. Nature 581: 221–224.

[15] Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q (2020). Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367: 1444–1448.

[16] Ibrahim M, Saleh NA, Hameed AJ; Elshemey WM, Elsayed AA (2010). Structural and electronic properties of new fullerene derivatives and their possible application as HIV-1 protease inhibitors. Spectrochim. Acta A 75: 702-709.

[17] Ibrahim M, Saleh NA; Elshemey WM, Elsayed AA (2010). Computational notes on fullerene based system as HIV-1 protease inhibitors. Comput Theor Nanosci 7: 224-227.

[18] Ibrahim M, Saleh NA, Elshemey WM, Elsayed AA (2012). Fullerene derivative as anti-HIV protease inhibitor: molecular modeling and QSAR approaches. Mini Rev Med Chem 12(6): 447-451.

[19] Kraevaya OA, Peregudov AS, Troyanov SI, Godovikov I, Fedorova NE, Klimova RR, Sergeeva VA, Kameneva LV, Ershova ES, Martynenko VM, Claes S, Kushch AA, Kostyuk SV, Schols D, Shestakov AF, Troshin PA (2019). Diversion of the Arbuzov reaction: alkylation of C-Cl instead of phosphonic ester formation on the fullerene cage. Org Biomol Chem. 17(30): 7155-7160.

[20] Sergeeva V, Kraevaya O, Ershova E, et al (2019). Antioxidant Properties of Fullerene Derivatives Depend on Their Chemical Structure: A Study of Two Fullerene Derivatives on HELFs. Oxid Med Cell Longev 2019: 4398695.

[21] Aquaro S, Scopelliti F, Pollicita M, & Perno CF (2008). Oxidative stress and HIV infection: Target pathways for novel therapies? Future HIV Therapy 2(4): 327-338.

[22] Ivanov AV, Bartosch B, Isaguliants MG (2017). Oxidative stress in infection and consequent disease. Oxid Med Cell Longev 2017: 3496043.

[23] Delgado-Roche L, Mesta F (2020). Oxidative stress as key player in severe acute respiratory syndrome coronavirus (SARS-CoV) infection. Arch Med Res 51: 384-387.

[24] Nielsen GD, Roursgaard M, Jensen KA, Poulsen SS, Larsen ST (2008). In vivo biology and toxicology of fullerenes and their derivatives. Basic Clin Pharmacol Toxicol 103(3):197-208.

[25] Dennington R, Keith T. and Millam J. GaussView, Version 5, Semichem Inc, Shawnee Mission KS, 2009. http://www.gaussian.com/g_tech/gv5ref/gv5citation.htm.

[26] ElHaes, H., Saleh, N.A., Omar, A., Ibrahim, M. (2014). Molecular spectroscopic study of fulleropyrrolidine carbodithioic acid. J Comput Theor Nanosci 11: 2136-2140.

[27] Hameed AJ, Ibrahim M, ElHaes H (2007). Computational notes on structural, electronic and QSAR properties of [C60] fulleropyrrolidine-1-carbodithioic acid 2; 3 and 4-substituted-benzyl esters. J Mol Struct-THEOCHEM 809: 131-136.

[28] Saleh NA, ElHaes H, Osman O, Mahmoud AA, Ibrahim M (2015). Spectroscopic analyses of modified fulleropyrrolidine derivatives. Open Spectrosc J 9: 1-6.

[29] Hostaš J, Řezáč J and Hobza P (2013). On the performance of the semiempirical quantum mechanical PM6 and PM7 methods for noncovalent interactions. Chem Phys Lett 568: 161-166.

[30] Řezáč J and Hobza P (2011). A halogen-bonding correction for the semiempirical PM6 method. Chem Phys Lett 506 (4-6): 286-289.

[31] Lan J, Ge J, Yu J et al. (2020). Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581: 215–220.

[32] Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004). UCSF Chimera- a visualization system for exploratory research and analysis. J Comput Chem 25(13): 1605-12.

[33] Morris GM, Huey R., Lindstrom W, Sanner MF, Belew RK, Goodsell DS and Olson AJ (2009). Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. J Comput Chem 16: 2785-91.

[34] Trott O, Olson AJ (2010). AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2): 455‐461.

[35] Antunes DA, Moll M, Devaurs D, Jackson KR, Lizée G, and Kavraki LE (2017). DINC 2.0: a new protein-peptide docking webserver using an incremental approach. Cancer Res 77: e55–57.

[36] Du X, Li Y, Xia Y-L, Ai S-M, Liang J, Sang P, Ji X-L, Liu S-Q (2016). Insights into protein–ligand interactions: Mechanisms, models, and methods. Int J Mol Sci 17: 144.

[37] Salentin S, Schreiber S, Haupt VJ, Adasme MF, Schroeder M (2015). PLIP: fully automated protein-ligand interaction profiler. Nucleic Acids Res. 43(W1): W443‐W447. doi:10.1093/nar/gkv315

[38] Hui KPY, Cheung M-C, Perera RAPM, Ng K-C et al. (2020). Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures. Lancet Respir Med S2213-2600(20)30193-4.

[39] Cao Y, Li L, Feng Z et al (2020).Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov 6: 11.

MetMe.png
Graphic representation of Interactions

Download PDF

Version 1

posted

You are reading this latest preprint version

Molecular Interactions of Fullerene-Based Derivatives and SARS-CoV-2

Status:

Version 1

Abstract

Figures

Introduction

Methodology

Results

Discussion

Declarations

References

Supplementary Files

Status:

Version 1