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Monoclonal Antibodies as Potential Treatment Drugs for Nsp15 and 3CL pro
Proteins

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DOI: 10.22036/pcr.2022.351595.2147

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Regular Article PHYSICAL
CHEMISTRY
RESEARCH
Published by the
Iranian Chemical Society
www.physchemres.org
[email protected]

Phys. Chem. Res., Vol. 11, No. 3, 623-629, September 2023

DOI: 10.22036/pcr.2022.351595.2147

Monoclonal Antibodies as Potential Treatment Drugs for Nsp15 and 3CLpro Proteins

S.O. Alshammaria, G.M. Al-Mazaidehb,*, F. Alakhrasc,*, M.A. Huneifd, S.I. Ali Shahe, A. Ahmadf,
H. Ayyal Salmang and M. Helmy Faris Shalayelh
a
Department of Biology, College of Science, University of Hafr Albatin, P. O. Box: 1803, Hafr Al Batin, Saudi Arabia
b
Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hafr Al Batin, P. O. Box: 1803, Hafr Al Batin 31991,
Saudi Arabia
c
College of Pharmacy, Middle East University, Amman, 11831, Jordan
d
Department of Pediatrics, College of Medicine, Najran University, Najran, Saudi Arabia
e
Department of Biochemistry, CMH Lahore Medical College & Institute of Dentistry, Lahore, Pakistan
f
College of Pharmacy, University of Hafr Al Batin, Kingdom of Saudi Arabia
g
School of Biological Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
h
Professor of Biochemistry, Department of Pharmacy Practice, University of Hafr Al Batin, Saudi Arabia
(Received 11 June 2022, Accepted 17 September 2022)

Selected monoclonal antibody molecules were conducted using the antibody-antigen docking mode, as well as the antibody-antigen
docking approach. The objective of the study was to check the effects of Cetuximab COVID-19 proteins (Nsp15 and 3CLpro) by using
antibody-antigen docking mode, as well as the antibody-antigen docking approach. The results of molecular docking revealed that Cetuximab,
a cancer-fighting antibody, ranks first among antibodies to both COVID-19 proteins (Nsp15 and 3CLpro). In cetuximab-3CLpro and
cetuximab-Nsp15 complexes, the antigen interacts with both antibody chains, H and L. According to the findings, Cetuximab can be added
to the COVID-19 treatment protocol, which may have the desired effect of inhibiting viral replication and decreasing mortality by targeting
COVID-19 proteins (Nsp15 and 3CLpro). Validation of these computational findings will require additional in vitro and in vivo research,
which can be considered as a contribution in the field of biotechnology.

Keywords: COVID-19, Antibody-Antigen docking, Cetuximab

INTRODUCTION spleen cells immunized with the target antigen to form a

hybridoma [3]. Polyclonal antibodies are produced by
Monoclonal antibodies originate from a single parent various B cells and recognize multiple epitopes on the same
clone of a single B cell; therefore, they recognize only one antigen [4].
epitope per antigen and are less likely to cross-react with Monoclonal antibodies are increasingly employed in the
other proteins as compared to polyclonal antibodies [1]. The treatment of various cancers and immunological disorders [5,
B cells, which produce specific monoclonal antibodies, are 6]. Their immunotherapeutic efficacy is based on three main
immortalized by fusion with the hybridoma cells, allowing mechanisms: (1) Antibody activation inhibits factors and
identical monoclonal antibodies to be produced over a long receptors that unlock signal pathways by dividing cancer
period of time [2]. Generally, the monoclonal antibodies cells and angiogenesis. (2) Antibody-dependent cell
are produced ex-vivo by mixing myeloma cells with mouse cytotoxicity consisting of target monoclonal antibodies
binding to specific tumor-related antigens, and
*Corresponding author. E-mail: [email protected] (3) Complement-dependent cytotoxicity by complement
 Al-Mazaideh et al./Phys. Chem. Res., Vol. 11, No. 3, 623-629, September 2023.

activation [6-8]. Even though monoclonal antibodies have pp1ab from SARS-CoV-2 (chain A of PDB ID: 6LU7 [19];
different modes of action, they have all become part of the 3CLpro protein) and (chain B of PDB ID: 6VWW [20]; Nsp15
standard treatment protocol in combination with protein). Selective monoclonal antibody compounds
chemotherapy and/or radiotherapy [9]. Monoclonal obtained from the DrugBank database
antibodies are laboratory-made proteins that imitate the (https://go.drugbank.com/) are listed in Table 1.
ability of the immune system to destroy dangerous antigens UCSF Chimera 1.15 [21] was used for modeling and
like viruses [10]. analysis processes. All mismatched residues were corrected
The coronavirus disease 2019 (COVID-19) pandemic to the right amino acids. Ligands and solvent molecules were
caused by SARS-CoV-2 virus has massively affected the removed from the receptor (or antigen) structures. Missing
whole world over the last few years [11]. SARS-CoV-2 is an hydrogen atoms were added, Dunbrack 2010 rotamer library
enveloped β-coronavirus whose viral envelope is coated by [22] was used for building incomplete side chains, Gasteiger
spike (S) glycoprotein, which mediates host cell binding and method [23] was used for assigning charges using
entry [12,13]. Most patients with SARS-CoV-2 infection
Antechamber [24], and the AMBER14SB force field [25]
(without advanced age or comorbidity) recover without
was used for standard residue parameterization. The default
treatment at variable rates, indicating the need to research
AMBER force field parametrization is to fulfill the
treatments in vulnerable patients who are most likely to
physiological pH condition (i.e., pH = 7.4) in each receptor.
benefit from early therapy [14,15]. Several SARS-CoV-2
That is, Asp and Glu residues were deprotonated, Arg and
monoclonal antibodies have reached clinical trials [16].
Lys residues were protonated, and His residues kept neutral.
Bamlanivimab is one such neutralizing IgG1 monoclonal
Molecular docking was conducted on the ClusPro server [26-
antibody that has been given emergency use approval (EUA)
30]using the antibody-antigen docking mode, and ROSIE
for use against SARS-CoV-2 infection [17]. It directly targets
server [31-36] using the antibody-antigen docking approach.
SARS-CoV-2 glycoprotein by binding to the glycoprotein’s
receptor-binding domain and is designed to neutralize the
virus by inhibiting viral attachment and entry into human
RESULTS AND DISCUSSION
cells [18]. This study aims to display and assess the potential
inhibitory activity of specific monoclonal antibody The objective of the study was to check the effects of
molecules against SARS-CoV-2 (3CLpro and Nsp15), with Cetuximab COVID-19 proteins (Nsp15 and 3CLpro) by
the hope of identifying new drugs to combat the new using the antibody-antigen docking mode, as well as the
pandemic coronavirus disease (COVID-19). antibody-antigen docking approach. We explored Cetuximab
can be added to the COVID-19 treatment protocol, which
METHODOLOGY may have the desired effect of inhibiting viral replication and
decreasing mortality by targeting COVID-19 proteins
The structures of coronaviral targeted proteins included (Nsp15 and 3CLpro).

Table 1. Selected Monoclonal Antibodies Used in the Docking Study

Abciximab DB00054 6V4P H Anticoagulant [37]

Adalimumab DB00051 4NYL H, L Anti-inflammatory To be published
Alemtuzumab DB00087 1CE1 H, L Anticancer [38]
Atezolizumab DB11595 5XXY H, L Anticancer [39]
Bevacizumab DB00112 6BFT H, L Anticancer To be published
Cetuximab DB00002 6AXP H, L Anticancer [40]
Eculizumab DB01257 5I5K H, L Anticoagulant [41]

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 Monoclonal Antibodies as Potential Treatment Drugs/Phys. Chem. Res., Vol. 11, No. 3, 623-629, September 2023.

Recent studies displayed that sundry monoclonal Abciximab > Eculizumab > Adalimumab > Alemtuzumab >
antibodies (mAbs) are forthright against the S protein Bevacizumab > Cetuximab > Atezolizumab. On the ROSIE
receptor binding domain of SARS-CoV-2 and could ban the server, the order of the antibodies according to rosetta energy
transmission of Covid-19 infection and defend subjects from unit (REU) at the interface is as follows: Cetuximab <
advanced severe conditions [16,42]. Eculizumab < Atezolizumab < Alemtuzumab < Adalimumab
Among the widely used tools for protein–protein docking < Bevacizumab. The antibody Abciximab has been excluded
is the ClusPro server [26-30] and the ROSIE server [31-36]. from the list because its structure does not have the L chain.
The ClusPro server uses the global search method for protein- On the other hand, and for the coronaviralNsp15 protein,
protein docking, which is useful when the binding site is the antibodies have the following order according to the
unknown, whereas the ROSIE server uses the local search ClusPro cluster size: Cetuximab > Alemtuzumab >
method for protein-protein docking; thus, the binding site Abciximab > Eculizumab > Adalimumab > Bevacizumab >
must be known. In our study, the original PDB structures of Atezolizumab. On the ROSIE server, the order of the
the antibodies and antigens have been entered into the antibodies according to rosetta energy unit (REU) at the
ClusPro server, and the outputs of the ClusPro server, after interface is as follows: Cetuximab < Bevacizumab <
determining the binding site, have been entered into the Atezolizumab < Adalimumab < Eculizumab <
ROSIE serve. The antibody-antigen docking results are Alemtuzumab. Again, the antibody Abciximab has been
shown in Table 2. excluded from the list because of the same previous reason.
For the coronaviral3CLpro protein, the antibodies are Because all these antibodies except Abciximab have
ranked according to the ClusPro cluster size as follows: typical rosetta energy unit values, that means they are good

Table 2. Antibody-antigen Docking Results Using Global and Local Methods

ClusPro results ROSIE results

(Global docking) (Local docking)
Antibody Antigen
Weighted score Score (REU)
Cluster size
Center Lowest energy Interface Total
pro
Abciximab 3CL 176 -326.1 -359.3 No L chain No L chain
Adalimumab 3CLpro 110 -258.3 -337.8 -9.026 -521.297
Alemtuzumab 3CLpro 106 -287.1 -287.1 -10.678 -582.486
pro
Atezolizumab 3CL 63 -314.6 -326.2 -11.561 -539.875
pro
Bevacizumab 3CL 70 -345.8 -349.6 -8.700 -586.144
Cetuximab 3CLpro 70 -286.0 -347.0 -13.764 -584.213
pro
Eculizumab 3CL 119 -249.3 -304.9 -12.125 -487.993
Abciximab Nsp15 59 -332.8 -334.4 No L chain No L chain
Adalimumab Nsp15 50 -273.6 -327.2 -8.443 -546.845
Alemtuzumab Nsp15 74 -275.0 -319.7 -7.535 -606.917
Atezolizumab Nsp15 45 -279.6 -343.5 -8.587 -584.094
Bevacizumab Nsp15 46 -308.6 -331.6 -9.319 -615.112
Cetuximab Nsp15 144 -371.6 -382.8 -10.287 -615.312
Eculizumab Nsp15 53 -257.0 -283.5 -8.149 -524.609

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 Al-Mazaideh et al./Phys. Chem. Res., Vol. 11, No. 3, 623-629, September 2023.

Fig. 1. Antibody-antigen complex. (a) Cetuximab-3CLpro complex and (b) Cetuximab-Nsp15 complex. Colors show the chains
of the antibody and antigen molecules: Chain H; blue, Chain L; red, and antigen; green.

decoys. However, it seems that Cetuximab, which is ACKNOWLEDGEMENTS

classified as an anticancer, has an outstanding rank among
the antibodies for both coronaviral proteins. The structures of Molecular graphics and analyses were performed with
the Cetuximab-3CLpro and Cetuximab-Nsp15 complexes are UCSF Chimera, developed by the Resource for
shown in Fig. 1. In both complexes, the antigen interacts with Biocomputing, Visualization, and Informatics at the
both antibody chains, H and L. University of California, San Francisco, with support from
NIH P41-GM103311.
CONCLUSIONS
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