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Drug Repurposing and Computational Drug Discovery: Strategies and Advances.
Mithun Rudrapal, PhD (Ed)
© 2024 Apple Academic Press, Inc. Co-published with CRC Press (Taylor & Francis)
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Drug Repurposing and Computational
Drug Discovery for Inflammatory
Diseases
VISHAL KUMAR SINGH, HIMANI CHAURASIA, JAYATI DWIVEDI,
RICHA MISHRA, and RAMENDRA K SINGH
ABSTRACT
Questing new molecular entities (NME) as drugs by traditional or de novo
approach of drug discovery is a lengthy, arduous, and expensive venture.
A powerful approach gaining momentum in pharmaceutical field regarding
novel drug discovery that restricts the search unto existing drug candidates
having authenticated and proven biological compatibility is the process of
drug repurposing. This eventually eliminates the prolonged clinical trials
and shortens the duration of drug availability under exigency conditions. It
amplifies the therapeutic importance of a drug and subsequently intensifies
the success rate. Thus, drug repositioning is an emphatic alternative tactic
to traditional drug discovery process. Outcomes of several clinical analyses
in therapeutics of inflammatory diseases alluded that the drugs acting via
synergistic inhibition of multiple targets were likely to be more successful
and promising. Keeping this hypothesis intact, this chapter dwells upon a
representative set of currently used computational approaches to identify
multi-targeted repositionable drugs for inflammatory diseases from a pool
of drugs primarily approved for other microbial infections. Furthermore,
a method to establish a successful relationship between computational
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Drug Repurposing and Computational Drug Discovery: Strategies and Advances
approaches and experimental studies is the integral part while focussing on
a unified drug repurposing strategy for better pharmaceutical and biological
results. The effective therapeutics thus developed may also act as promising
agents in averting drug resistance.
For more than a decade, a paradigm swing in drug development strategies
unambiguously linked with a better mechanism of disease biology has been
recorded, which permits better treatment of crucial diseases using targeted
1,2
therapies.
Usually, a high attrition rate increases the duration of the
development of new drugs and this factor becomes a major challenge for
the pharmaceutical industries.3 Acute or chronic inflammatory diseases pose
a serious threat and an advanced level of scientific challenge that requires
untiring efforts in developing anti-inflammatory drugs.
4,5
Inammation is one of the common events in the majority of acute as well
as chronic debilitating diseases that represents a major cause of morbidity
in the contemporary era of modern lifestyles.6 It plays a very important
role in the pathogenesis of various diseases such as allergies, atherosclerosis, rheumatoid arthritis, asthma, autoimmune diseases, coeliac disease,
glomerulonephritis, hepatitis, inammatory bowel disease, proper fusion
injury, transplant rejection, and cancer. Inammations involve immune cells,
molecular mediators, and blood vessels as a protective response. It promotes
the elimination of the initial cause of cell injury and also initiates tissue repair.
Inammatory mediators such as TLR-4, TLR-2, iNOS, and interleukins (ILs)
drive the inammation process.7 Traditionally, drugs against inammatory
diseases were isolated from certain plants, and their extracts were used for
relief from inammations, fever, and pain. In the mid-19th century when
salicylate, an anti-inammatory agent, was discovered as the active form of
Willow Spp., which triggered its synthesis, and then the acetylsalicylic acid
or aspirin trademark was developed. The lack of anti-inammatory drugs
and vectors provokes the need for developing new molecules for the treat-
ment of inammatory disorders.8 Current approaches to overcome inammation include the use of non-steroidal anti-inammatory drugs (NSAIDs),
immune selective anti-inammatory derivatives, selective glucocorticoid
receptor agonists, resolvins/protectins, and TNF inhibitors.9 These drugs
are presently used in the treatment of diseases where cytokines and other
non-prostaglandin components of chronic inammatory and neurodegenerative diseases are manifested. Although drug treatment has been improved
133
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to some extent, it is still a challenge for pharmaceutical chemists to explore
more effective, potent, and safe therapeutic regimens to treat inammation
and reduce the signs and symptoms of acute inammation and chronic
inammatory diseases.
Developing novel inammatory drugs with high efcacy may require a
longer duration of research and development efforts. However, seeing the
urgent need for drugs against inammatory diseases, repurposing the existing
drugs and focusing on the target may play an important role as it may lead
to the development of a rapid and efcient method for combating fatal infections. This screening strategy of the existing drugs has various advantages
over de novo drug development like it reduces the cost and associated risks
as the pharmacokinetic data with toxicity proles are already available.
Presently, many scientic groups are working on using the concept of
both drug-associated and disease-associated gene sets to identify the novel
uses of the existing drugs. The uses of amino acid sequences of target
proteins, chemical structures, and chemical protein interaction networks
can be utilized to nd new molecular target proteins for the existing drugs.
Several computational methods, such as molecular docking and dynamics
simulations have proved to be very promising in identifying the novel target
of the existing drugs in the current scenario. More than 10 online or licensed
platforms are currently available for such types of simulations. Among
them, Discovery Studio (DS) software for molecular docking studies and
GROMACS software for molecular dynamics (MD) simulations are the
most trending ones. These software packages are very useful in predicting
the interactions between the existing drugs and target protein receptors and
in studying the stability of the ligand-protein complexes.
10
The present book chapter focuses on discussing the repurposed drugs used
for the treatment of inammatory diseases and possible in silico approaches
for the identication of the existing drugs as anti-inammatory agents, and
the design and development of newer drugs against inammatory diseases.
The advancement in the system of healthcare is helpful in the early diagnosis of various diseases. It also decreases the death rate and increases the
life of the individual patient. For the past few centuries, clinical medicine
complexity has been drastically increasing, leading to continuous refinement in the measurement of non-fatal health loss. As new diseases are rising,
134
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
diagnostic categorization structure is expanding and the disability metrics
are becoming better.
11
The incidence of inammatory disease burden is rising all over the world
along with variations in disease trends in different regions in different countries. According to the data from the Global Burden of Diseases, Injuries,
and Risk Factors Study (GBD) 2017, inammatory disease cases reported
in 2017 were 6.8 million. This rate has been increasing in age-standardized
incidences from 79.5 (1990) to 84.3 (2017) per 100,000 population. However,
the rate of death is decreasing from 0.61 (1990) to 0.51 (2017) per 100,000
population. Country-wise, the highest rate of age-standardized incidence has
been recorded in the USA (464.5), and then the UK (449·6). The total year
lived with a disability is almost double in inammatory diseases from 0.56
million (1990) to 1.02 million (2017).
12
Patients with inammatory diseases are marked with the improved condition by introducing biological therapy using anti-TNF. Various antibodies of
anti-TNF are approved in the USA and Europe for the clinical therapy of
inammatory diseases. However, lots of patients have to drop the treatment
because of primary or secondary resistance caused within the year of the start
of treatment. There are various factors such as pharmacological, clinical,
patient-related, etc., identied as resistance to anti-TNF therapy (Fig. 6.1).
FIGURE 6.1 Schematic presentation of factors responsible for resistance during
inflammation therapy. CD4, cluster of differentiation 4; CRP, C-reactive protein; FCGRA, Fc
fragment of IgG receptor IIIa; HLA-DQA, human leukocyte antigen-DQ alpha; TNF, tumor
necrosis factor.
135
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Considering the high attrition rates, hefty costs and slow pace of de
novo drug discovery and development, repositioning of available drugs to
treat both prevalent and rare diseases is becoming a flourishing proposition
as it involves the usage of compounds with potentially shorter development
timelines and lower development costs
(Fig. 6.2).
FIGURE 6.2 Step-wise process of drug repurposing.
Generally, a drug repositioning approach consists of three steps—the
rst being the identication of a plausible candidate molecule (hypothesis
generation), the second step is the mechanistic assessment of the drug in the
preclinical model, and lastly, efcacy evaluation in phase II clinical trials
(only if there is sufcient data regarding safety and toxicity from phase I).
Of these three steps, the rst step is where modern approaches for generating
hypotheses could be most signicantly used for the identication of the appro-
priate molecule for a particular interest. These systematic approaches can be
classied into experimental approaches and computational approaches, both
of which are elaborately used (Fig. 6.3). On the basis of clinical data, drug
repurposing is encompassed into two broad categories. These approaches
have led to the identication of a number of plausible drug candidates, some
of which are already approved for disease and some are in advanced clinical
stages.
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Drug Repurposing and Computational Drug Discovery: Strategies and Advances
FIGURE 6.3 Approaches used in drug repurposing.
An inammatory response is mainly to protect the host from infection and
injury and to maintain homeostasis of the body which is a reex process.
Generally, ailment and fatality are primarily caused by inammatory disor-
ders such as allergies, asthma, autoimmune diseases, and sepsis.
By the use of zebrash screening, 251 drugs have been identied with
signicant anti-inammatory effects. This includes 22.4% of the drugs avail-
able in the library. Out of these, 43.9% are NSAIDs and 51.9% are corticosteroids.
14
Some repurposed drugs showing anti-inammatory properties are
listed in Table 6.1.
TABLE 6.1 Repositioned Drugs for Targeting Various Diseases.
S. Medicine Original indication Repurposed for
No.
1
Artemisia apiacea Hance
2 Methylthiouracil (MTU) Thyroid Sepsis
3 Methotrexate Cancer Rheumatoid arthritis
Malaria Atopic dermatitis (AD)
13
TABLE 6.1 (Continued)
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S. Medicine Original indication Repurposed for
No.
4 Topiramate Epilepsy Inflammatory bowel disease
5 Niflumic acid Analgesic Osteoarthritis and rheumatoid
arthritis
6 Heparin Anti-coagulant/heart Asthma
attack
7 Mangiferin Cancer Sepsis
8 Rifampicin Anti-biotic AD
9 Simvastatin Heart attack Sepsis and asthma
10 Rapamycin Anti-tumor Asthma
Anti-inflammatory drugs that have been repurposed for various types of diseases such as
sepsis, asthma, AD, etc., are discussed in this section.
6.3.1 REPURPOSING DRUGS FOR SEPSIS
137
Sepsis is a systematic inflammatory response induced mainly by infection.
Since 2001, FDA-approved, recombinant-activated protein C (APC), was
the only available drug for sepsis and septic shock therapy. Later, in October
2011, as a result of side effects and lack of efficiency, APC was withdrawn,
15
hence search for novel therapeutics against sepsis is still a necessity.
Drug repurposing can be utilized in severe situations where the currently
prescribed drugs are not efficient.
16
Some common repurposed drugs for
sepsis are discussed below.
MTU, an antithyroid drug was introduced as a thionamide for the treatment
16–18
of hypothyroidism.
The anti-septic effect of MTU could be due to its
ability to inhibit the release of high mobility group box 1 protein (HMGB1)
19
and HMGB1-mediated inflammatory responses.
It has been repurposed
for the treatment of sepsis involving multiple organ failure by CLP (cecum
ligation and puncture) such as renal injury, liver injury, and overall tissue
16
injury.
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Drug Repurposing and Computational Drug Discovery: Strategies and Advances
It is adopted for the treatment of hypercholesterolemia and hypertriglyceridemia. It lowers cholesterol synthesis by the inhibition of 3-hydroxy3-methylglutaryl-CoA reductase and is significantly used in hyper-lipidermia
20
to lower the risk of atherosclerotic complications.
Simvastatin has been
repurposed as an anti-sepsis drug and has displayed improvement in survival
rates of patients with multiple organ dysfunction syndrome.
21
Simvastatin
has displayed signs of the prevention of loss of integrity of the blood–brain
barrier (BBB), caused by polymicrobial sepsis. Additionally, it has antiinflammatory and anti-oxidative properties.
Mangiferin possesses antioxidant, immunomodulatory, antitumor, and anti-
22
viral activities.
Additionally, it has been adopted for hypoglycemic activity.
It has been repurposed for treating sepsis-induced acute kidney injury (AKI),
which includes inflammatory reactions by systemic cytokine storm or the
production of local cytokines.
6.3.2 REPURPOSING DRUGS FOR ASTHMA
Complex and multifactorial pathogenesis has been reported for asthma
which has affected over 300 million people globally. Primary mediation of
inflammatory response in asthma is by Th2-lymphocytes which are characterized by the production of Th2 cytokines, mucus hypersecretion, pulmonary eosinophilia, expression of inflammatory factors, and allergen-specific
23,24
immunoglobulin E (IgE).
Th2 cytokines and IgE play a significant role
in allergic asthma causing airway inflammation, airway hyperreactivity, etc.
Some common repurposed drugs for asthma are discussed below:
It is used to treat a rare lung disease called lymphangioleiomyomatosis
and in preventing organ transplant rejection. Due to mTOR inhibition, this
compound displays immunosuppressive functions and antiproliferative
properties. It has been repurposed in the new clinical regimen for asthma.
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Suppression of allergen-induced IL-13 and leukotriene levels has been
reported for rapamycin. In addition to this, IL-13, and IgE are completely
reduced by rapamycin.
25
Heparin is an anticoagulant and is primarily used in the treatment of arterial thromboembolism and to prevent deep vein thrombosis. Additionally,
it has been used in the treatment of heart attacks and unstable angina. Antiinflammatory properties, including asthma, have been reported in various
low molecular weight heparin (LMWH).
6.3.3 REPURPOSING DRUGS FOR ATOPIC DERMATITIS
AD is an inflammatory skin disorder, and it is accompanied by increased
26,27
serum levels of IgE due to increased inflammatory infiltration.
Mast
cells release histamine which is responsible for hypersensitivity and has the
potential as a vasoactive agent. Some common repurposed drugs for AD are
discussed in the following.
Rifampicin is used to treat various types of bacterial infections such as
and play a key role in relieving neuropathic pain and helping in immune
modulation. Rifampicin showed a decrease in the elevated serum levels of
IgE and IL-4, which consequently led to anti-AD activity.
28
It is a traditional medicine used to treat fever, eczema, and jaundice mostly in
east Asian countries like China, Korea, and Japan. Artemisinin was isolated
and developed as an active antimalarial drug. The repurposing of A. apiacea
29
in the treatment of dermatitis was demonstrated.
Proinflammatory cytokines
and chemokines expression was found to be regulated by ethanolic extracts
of A. apiacea Hance (EAH) in allergic inflammation. EAH are reported to
inhibit the formation of chemokines and pro-inflammatory cytokines.
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