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\begin{document}

\title{Rimantadine: A potential drug for COVID-19}



\author[1]{Richard Njunge}%
\affil[1]{Kabarak University}%


\vspace{-1em}



  
  \date{June 15, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background and purpose: Coronavirus disease 2019 (COVID-19) caused by
Severe Acute Respiratory Syndrome- Coronavirus 2 (SARS-CoV2) is a highly
contagious disease that has infected more than 200,000 patients and led
to more than 10000 deaths in 166 countries in less than four months. New
medications are needed to combat this disease. Since the process of
discovery, development and approval of new drugs is long, old drugs can
be repurposed for treatment of COVID-19. Oseltamivir is used for
management of COVID-19 and Influenza A. Rimantadine is an alternative
drug to oseltamivir for management of influenza A. Therefore, it is
possible that rimantadine can be used for management of COVID-19 as an
alternative to oseltamivir. The purpose of the study is to verify the
potential of rimantadine as a drug for COVID-19 Methods: The SARS-CoV2
nucleocapsid was downloaded from the Protein databank and the chemical
structure of rimantadine downloaded from Pubchem. Molecular docking of
the nucleocapsid as the receptor and rimantadine as the ligand was done
using avogadro and chimera software. Prediction of pharmacokinetic
properties was done using SWISSADME website while the toxicity
properties predicted using the ProTox server. Results: The interactions
between rimantadine and the SARS-CoV2 nucleocapsid involved conventional
hydrogen bonding with threonine \& asparagine; attractive charge
interaction with aspartate and Pi-alkyl interaction with tryptophan.
Rimantadine has high gastrointestinal activity, very few drug-drug
interactions and is relatively safe. Conclusion: Rimantadine binds to
the SARS-CoV2 nucleocapsid and can thus be used for management of
COVID-19. Keywords: Rimantadine, COVID-19, SARS-CoV2, Oseltamivir%
\end{abstract}%



\sloppy


\textbf{Introduction}

Coronavirus disease 2019 (COVID -19), a highly infectious condition
caused by Severe Acute Respiratory Syndrome- Coronavirus 2 (SARS-CoV2),
was initially reported in Wuhan, China in December 2019 (Wu \emph{et
al.} , 2020)(Zhu \emph{et al.} , 2020)(Wang \emph{et al.} , 2020). It
was declared a pandemic by the World Health Organisation (WHO) on
11\textsuperscript{th} March 2020 (Hageman, 2020). Based on an
interactive web-tool created by Centre for Systems Science and
Engineering at John Hopkins University, the number of confirmed cases as
at 21\textsuperscript{st} March 2020 was 287, 239. The total deaths
stood at 11, 921 (Dong, Du and Gardner, 2020). Within less than four
months, COVID-19 had already infected patients in 167 countries (Dong,
Du and Gardner, 2020). New drugs are needed to curb the COVID-19
pandemic due to lack of specific antivirals for COVID-19 (Lu, 2020).
However, due to the long process of drug discovery, approved drugs for
other conditions can be tested for efficacy against COVID-19 (Lu, 2020).

SARS-CoV2 is a beta-coronavirus whose major structural genes are
transcribed and translated to form a small membrane protein, spike
protein, the nucleocapsid protein and a membrane glycoprotein (Velavan
and Meyer, 2020). These proteins are potential targets for drugs to be
used in management of COVID-19. The nucleocapsid protein of SARS-CoV2
binds viral RNA genome and thus affects replication and transcription.
It can be targeted for development of potential drugs (Chen \emph{et
al.} , 2020).

Rimantadine (\selectlanguage{greek}α --\selectlanguage{english}methyl-1- adamantane methylamine hydrochloride), a
relatively safe antiviral, is effective for prevention and treatment of
influenza A infections especially when neuraminidase inhibitors like
oseltamivir are contraindicated (Alves Galv\selectlanguage{ngerman}ão, Rocha Crispino Santos and
Alves da Cunha, 2014). Rimantadine inhibits the M2 protein of influenza
A and thus inhibits the uncoating of the nucleocapsid of the virus
(Intharathep \emph{et al.} , 2008) (Wang, Wei and Chou, 2009). It is a
cheaper alternative to oseltamivir in management of influenza A (Smith
and Roberts, 2002)(Lynd, Goeree and O'Brien, 2005). Oseltamivir has also
been used for management of COVID-19 (Velavan and Meyer,
2020)(Lai\emph{et al.} , 2020; Lee \emph{et al.} , 2020). Therefore,
since rimantadine has been used as an alternative for oseltamivir in
management of influenza A infection, then it is plausible that it might
also be used as an alternative in management of COVID-19.

\textbf{Methods}

In-silico drug analysis was done.

The 2-D structure of rimantadine was downloaded from PubChem
(https://pubchem.ncbi.nlm.nih.gov/\emph{)} . It was converted to the 3-D
structure by Avogadro software (Hanwell \emph{et al.} , 2012). By using
the Avogadro software, the 3-D structure was then optimised to the most
stable conformation by using MMFF94s as the force field. The 3-D stable
structure of rimantadine was saved. With the help of Chimera software,
hydrogen atoms and charge were added to the stable conformation of
rimantadine (Yang \emph{et al.} , 2012).

The Protein Databank (PDB) (https://www.rcsb.org/\emph{)} was used to
access the RNA binding domain of nucleocapsid of SARS-CoV2 (PDB ID:
6VYO). This nucleocapsid was downloaded and residues removed by the
Chimera software (Yang \emph{et al.} , 2012). Surface - binding analysis
was carried out between rimantadine and the nucleocapsid of SARS-CoV2
using AutoDock vina feature in the Chimera software. The receptor-ligand
interactions were observed using Discovery Studio software.

For comparison purposes, the Influenza A M2 protein (PDB ID: 6BKK) was
downloaded from PDB and residues removed. The binding properties between
rimantadine and the M2 protein of influenza A were assessed using the
AutoDock vina feature in Chimera software.

The pharmacokinetic profile of rimantadine was predicted using SWISSADME
online tool (http://www.swissadme.ch/) (Daina, Michielin and Zoete,
2017). This online tool assists in predicting and evaluating
drug-likeness, pharmacokinetic properties and medicinal chemistry
likeness. The canonical SMILES of rimantadine were inserted on the
SWISSADME website and the potential absorption, distribution, metabolism
and excretion properties predicted.

The toxicity profile of rimantadine was predicted using the ProTox
server: http://tox.charite.de/protox\_II/ (Banerjee \emph{et al.} ,
2018). Canonical SMILES of rimantadine were inserted in the ProTox
server and the toxicity profile of the compound was predicted. ProTox
server predicts oral toxicity, organ toxicity especially hepatotoxicity,
toxicological endpoints (carcinogenicity, mutagenicity, immunotoxicity
and cytotoxicity), toxicological pathways (nuclear receptor signaling
pathways -- 7 models and stress response pathways -- 5 models) and 15
toxicity targets based on Novartis in vitro safety panels.

\textbf{Results}

Rimantadine binds to the nucleocapsid of SARS-CoV2 as shown in Figure 1.
The highest binding energy for the rimantadine-SARS-CoV2 nucleocapsid
complex was -7.5 which was slightly more optimal compared to the highest
binding energy for rimantadine-influenza A M2 protein complex which was
-7.3.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1: Receptor binding of Rimantadine on Nucleocapsid SARS-CoV2

The interactions between rimantadine and the SARS-CoV2 nucleocapsid
involved conventional hydrogen bonding with threonine at position 57 in
chain A, asparagine at position 77 in chain B; attractive charge
interaction with aspartate at position 82 in chain B and Pi-alkyl
interaction with tryptophan at position 52 in chain B. These
interactions are demonstrated in Figure 2.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2: Interactions of Rimantadine and Nucleocapsid of SARS-CoV2

In silico pharmacokinetic analysis indicated that rimantadine had high
gastrointestinal absorption, crosses the blood brain barrier, is not an
inhibitor of either cytochrome P450 isoform 1A2,2C9,2C19, 2D6 or 3A4.
The bioavailability score was 0.55 indicating absorption rate of
approximately 55\%. Rimantadine complies to Lipinski, Ghose, Veber and
Egain rules on druglikeness.

Toxicity prediction resulted in median lethal dose (LD50) of 157mg/kg
thereby classifying it in toxicity class 3 (LD50 between 50 and 300).
Rimantadine had no effect on hepatotoxicity, carcinogenicity,
immunotoxicity, mutagenicity and cytotoxicity. In terms of toxicity
targets, the effects are as shown in Table 1.

\textbf{Table 1: Effect of Rimantadine on Toxicity Targets}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Toxicity target\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Effect\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Aryl hydrocarbon Receptor\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Androgen Receptor\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Androgen Receptor -- Ligand Binding Domain\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Aromatase\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Estrogen Receptor alpha\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Estrogen Receptor -- Ligand Binding Domain\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Peroxisome Proliferator Activated Receptor Gamma\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Nuclear factor (erythroid derived 2) like 2/ antioxidant responsive
element\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Heat shock factor response element\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Mitochondrial membrane potential\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Phosphoprotein p53\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
ATPase family AAA domain containing protein 5\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
No effect\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Opioid receptor mu\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Probable binding\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Discussion}

This data indicates that rimantadine has a higher affinity for SARS-CoV2
nucleocapsid compared to influenza A M2 protein based on a more negative
binding energy. Rimantadine normally binds to the Influenza M2 protein
and ensures that the closed conformation of the M2 protein pore is
stable. One of the ways it ensures stability of the pore is by
interacting with the amino acid tryptophan at position 41 which forms
part of the gate of the M2 protein pore (Schnell and Chou, 2008).
Interestingly, rimantadine interacts with tryptophan at position 52 of
the nucleocapsid of SARS-CoV2 as shown in Figure 2. Serine (a
hydroxyl-containing amino acid) at position 31 of the influenza A M2
protein interacts with the charged hydrogen bonds of the amine group of
rimantadine (Intharathep \emph{et al.} , 2008). The interactions between
hydrogen bonds of the amine group of rimantadine and nucleocapsid of
SARS-CoV2 involve threonine (a hydroxyl-containing amino acid) at
position 57 and asparagine at position 77. These interactions indicate
the potential binding of rimantadine to nucleocapsid of SARS-CoV2 and
thus its potential use in management of COVID-19.

Prediction of rimantadine pharmacokinetics revealed that it has high
gastrointestinal absorption which is in agreement with a human study
done by Capparelli (Capparelli \emph{et al.} , 1988). Rimantadine
crosses the blood brain barrier and this would explain the central
nervous system side effects reported by Tominack in 1988, Guay in 1994
and Galvao in 2014 (Tominack \emph{et al.} , 1988) (Guay, 1994) (Alves
Galv\selectlanguage{ngerman}ão, Rocha Crispino Santos and Alves da Cunha, 2014). Predicted
bioavailability of rimantadine was 55\%. A study done by Wills reported
that following administration of a 100mg single dose of rimantadine, the
bioavailability of the tablet formulation was higher than that of the
syrup formulation but bioavailability for both formulations was still
high (Wills \emph{et al.} , 1987). Therefore, rimantadine can be
administered either as a tablet or a syrup. Rimantadine does not inhibit
cytochrome P450 isoforms CYP 1A2,2C9,2C19, 2D6 or 3A4. Lack of
inhibition of cytochrome P450 demonstrates less or minimal effect on
metabolism of other drugs and hence reduced effect on the
pharmacodynamics of these drugs. This indicates that the drug has
minimal drug-drug interactions.

Toxicity prediction revealed that rimantadine is a relatively non-toxic
drug with a median lethal dose of 157mg/kg. According to Wills (1987),
Tominack (1988), Guay (1994) and Galvao (2014), rimantadine is well
tolerated and has few side effects which involve the gastrointestinal
system and the central nervous system (Wills \emph{et al.} , 1987;
Tominack \emph{et al.} , 1988; Guay, 1994; Alves Galvão, Rocha Crispino
Santos and Alves da Cunha, 2014). Rimantadine probably binds to the
opioid mu receptor and thus can mediate analgesia (Vaught, Rothman and
Westfall, 1982). Another study demonstrated that rimantadine inhibits
NMDA receptors and can thus also be used for parkinsonism while yet
another reported that it has trypanocidal properties (Singer \emph{et
al.} , 2005; Torres \emph{et al.} , 2012).

\textbf{Conclusion}

Rimantadine has a high affinity for the SARS-CoV2 nucleocapsid and thus
can be used for management of COVID-19.

\textbf{Recommendations}

In vitro and in vivo studies need to be done to ascertain the efficacy
of rimantadine against SARS-CoV2.

\textbf{Competing interests}

None.



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