Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5649_Библиотеки_им_академика_М_И_Перельмана
.pdf
60
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
favipiravir, ritonavir, arbidol, darunavir, chloroquine, hydroxychloroquine,
and tocilizumab. In this chapter we have focused on the ongoing research
on the efficiency of repurposing drugs for the novel coronavirus through
experimental studies based on in-vitro, in-vivo analyses. An approach to
design new drugs/inhibitors will also be focused through CADD approach.
Viruses are a broad category of microorganisms that cause life-threatening
infections. Many antiviral medicines that target viral proteins or host factors
have been produced effectively over the last 30 years. Chronic viral infectious disorders such as HIV, influenza, hepatitis C virus (HCV), picorna
viruses, and corona viruses (SARS-CoV-2), and the rise in need for novel
antiviral medicines are mostly due to the development of resistance to
existing antiviral drugs. The increasing understanding of the molecular
mechanics of infection has paved the way for the development of novel
antiviral medicines that target specific viral proteins or host components.
The demand for novel antiviral medications in the treatment of chronic
infectious illnesses, as well as the emergence of more efficient new viruses,
drives research into new targets and processes for antiviral development.
1
Only 21 novel antiviral medications were approved by the Food and Drug
Administration (FDA) in the United States between 2012 and 2021, with
eight of them being for the treatment of hepatitis C virus (HCV)-related
pathologies and seven being used as anti-HIV drug (www.fda.gov). At the
same time, governments, and the World Health Organization (WHO) are
grappling with the worldwide danger of a slew of new and re-emerging
viruses that have caused worrying outbreaks in recent years. Many new
viruses are emerging, such as Zika virus (ZIKV), Ebola virus (EBOV),
2
and SARS corona virus. During the last of couple of years researchers have
taken deeper dig into repurposed drugs. The process of finding new uses
outside the scope of the original medical indication for existing drugs is
also known as redirecting, repurposing, repositioning, and re-profiling. The
problem in productivity and worldwide pressure on increasing prices and
the growing number of regulatory hurdles one must pass through many
drug developers to find new uses and new different targets as redirecting,
repurposing, repositioning, and re-profiling are all terms for the process of
identifying new applications for existing medications outside their original
medical indications. The challenge of productivity, global pressure on
rising pricing, and an increasing number of regulatory impediments must be
61 Viral Infections and Coronavirus Disease-2019
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
overcome by many drug researchers to identify new applications and new
targets as improved versions of current treatments are improvised version
of the already existing drugs
.3 Traditional drug development is difficult,
expensive, and time-consuming. Drug repurposing decreases the time and
cost of drug development for contagious diseases dramatically. The efficiency of developed drugs targeting viral proteins and host components is
limited by the resistance viruses and gives unfavorable side effects.4 The
drug repurposing strategy is the process of identifying new indications for
already-approved FDA treatments and is a potential way to boost up the
drug discovery process for viral diseases and a variety of other disorders.
5
Drug repurposing is critical in the fight against quickly spreading diseases
including HIV, influenza, hepatitis C, Ebola, dengue fever, Coronavirus,
and a variety of other fatal diseases.
6
Aside from the evident financial
benefit, drugs discovery using the Drug Repurposing strategy can swiftly
enter the clinical trials, especially for the contiguous diseases having no
specific therapy. The drug repurposing technique provides a steady flow of
information for studying viral biology and unknown molecular pathways.
Present drugs with previously unknown antiviral activities can be used to
explore viral mechanisms and pathology.7 Although there are a few drawbacks to the drug repurposing approach, such as difficulty in identifying
the target because the drug may have poly-pharmacology, the effective
concentration being higher than what can be achieved in human plasma,
and intellectual property rights issues, drug repurposing is still a better
8
approach because it has the potential to reduce research time and costs
.
In recent research, computational approaches have been widely used to
anticipate novel therapeutic targets or drug repurposing prospects (Fig. 3.1).
In comparison with wet lab experiment, computational high-throughput
screening such as structure-based drug screening, deep-learning (DL)-based
drug screening, and artificial-intelligence (AI)-based screening, in silico
techniques are faster, less expensive, and can serve as an initial filtering
step for thousands of molecules for lead structure identification9 and farther
modification with experimental confirmation. This necessitates the use of
appropriate algorithmic tools to explore disease-relevant or disease-specific
mechanisms. Antiviral capabilities of several drugs that were originally
produced for a disease or disorder are being investigated to combat the
worldwide problem of new and re-emerging viral diseases. Table 3.1
presents a list of pharmaceutical products that have been repurposed for
a specific ailment, as well as the original indication for which they were
produced.
7
62
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
FIGURE 3.1 The workflows of virus-targeting computational drug repurposing approaches.
The input data consist of protein structure information (experimental or predicted) and
chemical structure of drugs from public databases. Computational approach for antiviral drug
discovery consisting of docking followed by molecular dynamics (MD) simulations. Finally,
the output data approaches the potential molecules.
Source: Reprinted with permission from Ref. [10]. © 2020 Elsevier.
TABLE 3.1 Approved and Candidate Drugs with Repurposing Potential as Antiviral
7
Agents.
Compound Status/indication Virus
Mycophenolic acid Approved/ ZIKV
immunomodulator
Daptomycin Approved/antibacterial ZIKV
Niclosamide Approved/antiparasitic ZIKV
Azithromycin Approved/antibacterial ZIKV
Novobiocin Approved/antibacterial ZIKV
Nanchangmycin Investigational ZIKV
Hippeastrine hydrobromide Investigational ZIKV
Sofosbuvir Approved/antiviral ZIKV
Ribavirin Approved/antiviral ZIKV
Chloroquine Approved/antimalarial ZIKV, MERS-, and SARS-CoV
Memantine Approved/treatment of ZIKV
Alzheimer’s disease
Prochlorperazine Approved/antiemetic DENV
Chlorcyclizine Approved/antihistamine HCV
Manidipine Approved/antihypertensive JEV, ZIKV, and HCMV
Favipiravir Approved/antiviral EBOV
63 Viral Infections and Coronavirus Disease-2019
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
TABLE 3.1 (Continued)
Compound Status/indication Virus
GS-5734 Investigational/antiviral MERS and SARS-CoV
Imatinib Approved/anticancer MERS and SARS-CoV
Chlorpromazine Approved/antipsychotic MERS and SARS-CoV
Chlarithromycin/naproxen Approved/antibacterial, Influenza
+ oseltamivir
Nitazoxanide Approved/antiparasitic Influenza, rotavirus, and
Raltegravir Approved/antiviral Herpesvirus
Lopinavir/ritonavir + Approved/antiviral MERS-CoV
interferon b-1b
Lopinavir/ritonavir Approved/antiviral HPV
anti-inflammatory, antiviral
norovirus
Computer-aided drug discovery/design (CADD) methods have been vital in
the development of therapeutically important small molecules for more than
three decades. There are two types of methods: structure-based and ligandbased. Structural-based approaches are similar to high-throughput screening
in that they require both target and ligand structure knowledge. Structurebased techniques include ligand docking, pharmacophore design, and ligand
docking. Using just ligand information, pharmacophores, molecular descriptors, and quantitative structure-activity connections, ligand-based approaches
predict activity based on its similarity/dissimilarity to previously known
11
active ligands.
The article outlines the theory behind the most essential
strategies as well as recent successful implementations of repurposed drug
screening as COVID-19 caused a large number of deaths in 2020, prompting
a global emergency. Vaccines were developed as a result of continuing
research and clinical trials. However, due to the evolving coronavirus, the
vaccine’s long-term effectiveness is still in doubt, which makes drug repositioning a realistic choice.12 In the aftermath of the Zika virus outbreak a
few years ago, one possible path to preventing viral epidemics is to identify
broad-spectrum antiviral medications that are effective against entire families of viruses, has been suggested by Dr Anthony Fauci, who is one of the
world’s foremost authorities on infectious diseases and the longstanding
director of the National Institute of Allergy and Infectious Diseases.
13
64
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
FIGURE 3.2 Antiviral strategy class viruses rely on infected cells to promote viral genome
replication and virus particle synthesis. As a result, infection is a critical stage in the virus’s
life cycle. Reverse transcriptase inhibitors are antiviral medications that prevent viral genome
replication, hence limiting the formation of new virus particles. They operate within infected
cells. Entry inhibitors, on the other hand, interact with existing virus particles outside of
cells to prevent infection. They aid in viral load reduction and have been shown to improve
preventive and therapeutic effects.
Source: Reprinted from Ref. [14]. © 2013 Smith, de Boer, Brul, Budovskaya and van der
Spek. https://creativecommons.org/licenses/by/3.0/
3.2.1 VIRUS-TARGETING APPROACHES
Each virus has its own structural characteristics, yet many therapeutically
significant viruses have essential characteristics that can be used to develop
broad-spectrum antiviral drugs (Fig. 3.2). Many viruses, for example, replicate their viral genomes in identical ways within infected cells, leading to the
15
creation of antiviral replication inhibitors.
The majority of virus-targeting
methods depend on structure-based drug and deep learning screening
methods, which use three-dimensional structures of target proteins to estimate
affinities or interaction energies of known chemical compounds with the
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
proteins. These procedures are referred to virus-targeting approaches, since
they were primarily utilized to find potential medications that target viral
proteins; however, they may also be used to host proteins.
16
Three main methodological workows in structure-based drug screening:
• Same target–new virus: The first option is when an antiviral drug
that is known to target a specific viral or cellular function/pathway
is found to possess activity against other viruses. Antiviral action is
based on structural homology and shared enzymatic characteristics
of the viral target, as well as shared virus reproduction pathways.
Antiviral RNA-polymerase inhibitors like favipiravir and Sofosbuvir
(used to treat influenza and HCV infections, respectively) demon
-
strated its repurposing capabilities against EBOV and ZIKV (Table
3.1). Another example, drugs (e.g., chloroquine) that interfere with
the late-stage entrance process of viruses like filo viruses and corona
viruses, which employ cellular endocytotic routes to enter the host
2
cell.
• Same target–new indication: This occurs when a pharmacological
target (i.e., a protein uria pathway that can be modulated by an
approved drug) is found to be essential in a pathogenic process
associated with a viral infection. In this case, the approved drug can
be exploited also as an antiviral therapeutic agent (new indication).
The case is exemplified by the anticancer drug imatinib that inhibits
17
cellular ABL-kinase
genic coronaviruses.
and was found to be also active against patho
18
-
• New target–new indication: This occurs when an approved drug with
established bioactivity in a specific pathway or mechanism is found
to have a new molecular target (i.e., it shows poly-pharmacology,
see Glossary) which is essential for virus replication. Examples are
antimicrobial agents (e.g., teicoplan in, ivermect in, itraconazole, and
nitazoxanide) that were found to have a target also in virus-infected
cells, whose inhibition has detrimental effects on viral replication.
19
Deep learning
(DL) models can predict binding affinities or docking scores
and have shown advantages over conventional docking protocols. While
standard docking protocols are limited to millions, DL approaches can
66
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
analyze billions of chemical compounds. This allows them to be applied to
whole databases, which increase the diversity of the tested compounds and
the likelihood of finding unconventional compounds.20 Furthermore, they
21,22
are capable of processing more physico-chemical features (Fig. 3.2)
and
can find features related to a nonfavorable docking.20 However, most of these
methods require datasets for training, which often come from real docking
simulations; thus, the performance of many DL-based approaches still relies
on the accuracy of the docking software used for training.
FIGURE 3.3 Workflow of deep learning docking
Source: Reprinted with permission from Ref. [22]. © 2021 John Wiley & Sons.
Deep docking was created by Ton et al., who used quantitative structure–activity relationship models to predict docking scores of drugs targeting
the SARS-CoV-2 3CLpro protein.
23
Because it docks specic subsets of
compounds, it uses fewer docking processes and can generate a smaller list
of compounds that are also rich in possible top hits.
Math DL is a technique created by Nguyen et al.24 that uses lowdimensional mathematical representations of drug–target protein complex
structures, which are then fed into DL algorithms to estimate drug–protein
complex binding energies. For SARS-CoV-2, the authors used experimental
binding afnity data from SARS-CoV ligand–3CL
pro
complexes from PDB
bind and SARS-CoV protease inhibitors as training data to predict binding
67 Viral Infections and Coronavirus Disease-2019
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
energies on DrugBank compounds for SARS-CoV-2 3CL
pro25
and do not
depend on docking software.
Molecule transformer–drug target interaction is a DL-based drug–target
26
interaction prediction model created by Beck et al.
It predicts afnities
using simplied molecular-input line-entry system (SMILES) with 51 repre-
sentations for pharmaceuticals and protein sequences as input. The model
was trained on commercially available antiviral drugs as well as viral target
proteins for SARS-CoV-2. Among the potential molecules discovered were
antiviral agents that had previously been used to treat SARS-CoV-2.
3.2.2 HOST-TARGETING APPROACHES
The goal of host-targeting techniques is to find drugs that interfere with host
pathways that contribute to viral pathogenesis, making them less susceptible
27
to drug resistance.
This strategy has been driven by research in molecular
virology and reached more advanced stages of the drug development progress
so far, with compelling potential advantages over existing antiviral strategies.
Thus, it provides a successful blueprint for broad-spectrum antiviral strategies developed from a materials science and engineering angle. In general,
using small-molecule inhibitors that target a host cell factor that is not under
genetic control of the virus can present a more difficult evolutionary task for
the virus to escape drug susceptibility. This approach contrasts with directacting antivirals that can bind a viral enzyme with high affinity, where a
single-point mutation at the drug’s binding site can result in loss of drug
efficacy. For example, broad-spectrum kinase inhibitors, which have been
approved for anticancer therapy, have demonstrated the potential to impair
intracellular viral trafficking and thus inhibit a wide range of viruses, such
as hepatitis C, dengue, and Ebola, that depend on this particular host cell
function.
28,29
In addition, SARS-CoV-2 infections can trigger a hyperreactive
immune response characterized by the excessive release of pro-inflammatory
cytokines and chemokines.
30
Thus, by targeting specific dysregulated pathways, a molecule that affects the host immune response can help critically
sick individuals with COVID-19.
31,32
• Signature-based approaches: Signature-based approaches primarily
utilize transcriptome datasets from samples infected with viruses
to identify candidate drugs through connectivity mapping, a wellestablished approach that relies on finding drug-induced expression
signatures exhibiting reverse profiles to a disease signature.
33,34
68
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
• Network-based approaches: Multiple data sources, such as virus–host
interactions, PPIs, co-expression networks, functional connections,
or drug–target interactions, are used in the general network-based
method used in drug repurposing research on COVID-19. To discover
important host protein targets or sections of the host interactome that
can be addressed, network-based techniques or topological measurements are used to the generated networks.
35
3.3.1 REPURPOSING IN ZIKA VIRUS INFECTION
The Zika virus (ZIKV) is a flavivirus that is transmitted by mosquitos and causes
severe birth defects and Guillain–Barré syndrome. There are no antiviral drugs
or vaccines available to treat ZIKA virus infection.2 Barrows and colleagues
examined a library of 774 FDA-approved drugs for their ability to prevent or
inhibit a newly identified ZIKV strain from infecting human HuH-7 hepatocyte
cells. Ivermectin, mycophenolic acid (MPA), and daptomycin were among the
roughly 24 possible anti-ZIKV molecules discovered in their investigation. The
immunosuppressants drug mycophenolic acid and the antibiotic, daptomycin
were the promising inhibitors of ZIKA virus replication.36 Xu et al. screened
roughly 6000 compounds using a high-throughput screening approach, including
FDA-approved pharmaceuticals, molecules in clinical trials, and pharmacologically active compounds. They detected over 100 chemicals in SNB-19 cells that
inhibited ZIKV-induced caspase 3 activation.37 Another study demonstrated that
the bacterial polyether nanchangmycin prevented ZIKV infection in a range of cell
lines and ex vivo embryonic mouse midbrain neuron-glia mixed cultures38 Chloroquine, a standard anti-inflammatory and antimalarial drug, has antiviral properties
against several viruses. In Vero, human brain microvascular endothelial cells, and
neural stem cells, this candidate also has antiviral efficacy against ZIKV. Without
causing cytotoxicity, chloroquine lowers viral replication, the number of infected
cells, and cell death caused by ZIKV infection. Sofosbuvir (C22FN3O9P) hasH
found to be active against ZIKV.
39
The most often used drugs in ZIKV therapy in
pregnant women are niclosamide and azithromycin, both of which have a high
effective concentration in human plasma.37 Hippeastrine hydrobromide, a natural
substance, has been found to be a powerful inhibitor of ZIKV infection and
microcephaly-related consequences. The discovery of new genes and pathways for
the creation of new antiviral drug molecules for ZIKV infection will be aided by
drug–target network analysis and functional validation. Developing novel highthroughput drug repurposing tests and using current functional genomics methods
29
69 Viral Infections and Coronavirus Disease-2019
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
to viral replication pathways is a possible avenue toward finding efficient antiviral
treatments for ZIKV and other infectious agents.
2
3.3.2 REPURPOSING IN EBOLA VIRUS INFECTION
Since the discovery Ebola virus in the late 1970s, it has caused multiple
outbreaks, the most recent of which, in 2014–2016, was the most worrying
owing to its scale and spread. Because of the urgent need for an effective
Ebola virus cure, researchers have been studying current medications as
prospective anti-Ebola virus pharmacological therapeutic agents, a process
known as drug repurposing or drug repositioning. In vitro and in vivo tests
40
of favipiravir against Ebola virus showed promising results.
Chloroquine’s
has also been found to be potent against Ebola virus in numerous in vitro
investigations with various cell types.41 Selective estrogen reuptake modulators toremifene and clomiphene are widely accessible and licensed for the
treatment of breast cancer and infertility, respectively. These drugs were
determined to have antiviral properties because they blocked Ebola virus
entry by more than 90% in vitro.
42
Amiodarone is a multi-ion channel blocker
that is commonly used to treat atrial fibrillation and ventricular tachycardia.
It has been found to be an effective Ebola virus inhibitor in a variety of cell
43
lines.
Among the many medications evaluated for anti-Ebola virus activity
in vitro and in vivo, azithromycin was shown to be a potent in vitro inhibitor
of the virus. A targeted drug combination approach led to the discovery of
many therapeutic combinations that operate synergistically to prevent Ebola
virus entrance.
44
3.3.3 REPURPOSING IN HIV, CMV, HSV, AND HCV INFECTIONS
HIV/AIDS is one of the world's deadliest pandemics. Since 1981, 26 million
people have perished, according to the World Health Organization and
45
1.6 million died only in the year of 2012.
Chloroquine and its hydroxyl
derivatives, hydroxyl Chloroquine, were found to inhibit HIV-1 replication
in various investigations.46 Human Cytomegalovirus is a prime example of
virus host adaptability and the potential of viruses to fully undermine cellular
physiological functions in infected cells. Several approved or investigational
drugs with an anti-Human Cytomegalovirus mechanism that differs from
existing drugs like statins, cardiac glycosides, antiparasitic drugs emetine and
nitazoxanide, kinase inhibitors, and the antihypertensive drug manidipine
Соседние файлы в папке Библиотека им академика М.И. Перельмана