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10
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
preprocessing of data, (2) feature extraction, (3) model fitting, and (4) evaluation.26 Machine learning techniques for drug repurposing include logistic
regression, neural network, random forest, support vector machine, and
deep learning for multiclass classification, binary classification, and values
27
prediction.
For logistic regression, similarity-based machine learning
framework like “PREDICT” uses integrated drug–drug similarity and
disease–disease similarity values as features by applying logistic regression
by assuming that similar drugs are generally linked with similar diseases and
vice versa.
drug class prediction by incorporating multiple data sources.
28
Similarly, “SPACE” also used logistic regression for therapeutic
29
Likewise,
Luo et al. proposed a new computational approach named “MBiRW” that
uses some broad similarity measures and algorithm of bi-random walk
(BiRW) to predict novel indications for specific drug by incorporating
features information of drug or disease with identified drug–disease associations. The similarity measures were developed to predict similarity of
drugs and diseases followed by their similarity network construction that
was then integrated into heterogeneous network with known drug–disease
association. Based on this network, the MBiRW algorithm predicts novel
drug–disease interaction.
30
For support vector machine (SVM) techniques,
Napolitano et al., in their work, predicted drug therapeutic class based on
similarity in gene expression, drug chemical structure, and molecular target.
31
Aliper and Plis used deep learning techniques with gene expression data to
predict therapeutic drug categories and showed that deep neural networks
(DNN) exceeded SVM after 10-fold cross-validation that signified a proof
for employing deep learning for drug discovery.
32
1.3.2 EXPERIMENTAL APPROACHES
Experimental approaches comprise target screening, cell-based assays,
animal model, and clinical aspects.
Protein-based techniques such as mass spectrometry, affinity chromatography have been employed to detect the binding associates for drugs. Cellular
thermo-stability assay (CETSA) is used for target mapping engaged in cells
using bio-physical principles that detect thermal stability of target proteins
4
through drug-like ligand which have suitable cellular affinity.
Chemical
11 Drug Discovery and Development
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genetics can similarly offer an improved understanding of the binding and
efficacy relationship in the cellular perspective. Many industries focus on
high-throughput direct binding/catalytic assays to analyze small-moleculekinase binding using a range of in vitro assays and organism-based assays
4
to create heat maps of biological interactions.
Karaman et al. performed an
in-vitro assay to analyze 38 kinase inhibitors contrary to 317 different human
protein kinases and as a result, they identified “3175” binding interactions.
33
In phenotypic screening, sequence of cell-based in vitro assays in 96 or 384
34
well-plates is used.
For instance, Corsello et al. utilized “PRISM” (profiling
relative inhibition simultaneously in mixtures) method that tracks the cell
proliferation during drug treatment by unique molecular barcodes. Cell line
proliferation will decrease with higher drug efficacy that ultimately results
in the reduction of a definite molecular barcode. They performed a viability
assessment of 578 samples of human cancer cell-lines from different tumor
types when given a treatment of more than 4500 drugs comprising hundreds
of nononcology drugs.
35
Animal model screening assays can also be exploited in drug repositioning.
This approach not only recognized the drugs against diseases but also
produced organ-toxicity and pharmaco-kinetic results as compared with
a cell-based screening assay. In a study, Ridges et al. utilized genetically
engineered T-cells comprising zebra fish as an animal model for the assessment of effectiveness of about 26,000 small molecules against leukemia and
reported that Lenaldekar (LDK), a T-cell proliferation inhibitor, exhibited a
noteworthy activity against several hematologic malignancies.
36
MODELS
Validation of drug repositioning outcomes can be done computationally
and/or experimentally. Computational validation can be done in a straightforward manner to evaluate AUROC (area under the receiver operating
12
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
characteristic) values, positive-predictive value (PPV)
37
sensitivity, and
specificity. Moreover, drug validity can be evaluated by comparing predicted
targets in Clinical Trials, PubMed, or electronic health records (EHRs).
Experimental validation includes in vivo and in vitro cell-based targeting
assays in a controlled situation and in an animal model such as clinical
trials.27 For instance, albendazole was identified as a repurposed candidate
drug for cancer treatment by validating through in vitro and in vivo experiments to treat liver and ovarian cancer.
38
REPURPOSED DRUGS IN DRUG DISCOVERY
Repurposed drugs are safe and cost less, making them market-friendly, take
less time for development, and have increased chances of approval and
success rates. Many drugs are currently being repurposed and are under
various stages of their clinical trials listed in Table 1.2 to prove their efficacy
against various diseases. Some of the approved and currently investigated
drugs for various diseases are discussed below.
1.5.1 DRUG REPURPOSING AGAINST CANCER
According to WHO statistics, 19.3 million new cases were reported in 2020,
and if the current trends continue, an estimated 30.2 million people will
be affected by 2040. Extensive research is being conducted in search of
anticancer drugs, and more than 10,000 clinical trials are being conducted
in a year, of which only 5% of the drugs entering Phase I are approved.
39
Nelfinavir, an inhibitor of HIV protease used to treat AIDS, has shown anticarcinogenic properties, which are now being extensively studied.40 Studies
have shown nelfinavir regulating cell cycle and inhibiting proliferation of
tumors in ovarian cancer cells by decreasing the levels of PCNA (proliferating cell nuclear antigen) and proteins involved in the cell cycle.41 Aspirin,
commonly used as an antipyretic and analgesic, is an NSAID (nonsteroid
anti-inflammatory drug)42 with well-established cardiovascular protective
properties. Aspirin is also known to effectively prevent thrombosis and
platelet aggregation via COX-1 inhibition and is currently being used to
treat thromboembolism in patients prone to cardiovascular diseases.43 From
recent studies, aspirin is known to inhibit the carcinogenesis-promoting
enzyme cyclooxygenase (COX),44 and numerous other studies support the
13 Drug Discovery and Development
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antineoplastic property of aspirin. Several clinical studies have shown an
increase in survival chances in colorectal cancer patients using aspirin.
45
Disulfiram, approved for the treatment of chronic alcoholism, has proven
an antineoplastic effect. It manifests its effect by interfering with processes
involving copper and zinc, and copper is vital for tumor angiogenesis.
46
Disulfiram treatment has also been effective against breast cancer cells
and glioblastoma cells and showed increased efficacy in cis-platin sensitive cancer cells in clinical trials.
47
Metformin, used for the treatment of
type II diabetes, has been linked with reducing cancer incidence through
many studies. Treatment with metformin has decreased cancer incidence
and mortality rate compared to patients in other forms of diabetic treat-
48
ment.
apoptosis rate,
cancer cells.
Clinical studies on prostate cancer cells showed an increased
49
while decreased cell proliferation was observed in breast
50
Thalidomide, first marketed as a morning sickness remedy
during pregnancy, was later approved for the treatment of ENL (erythema
51
nodosumleprosum) in 1998 by FDA.
Later, thalidomide was shown effective against multiple myeloma.52 Celecoxib, an NSAID approved by FDA
in 1999 for arthritis treatment, has shown promising antitumor activity in
various types of cancer, especially breast cancer.
54
approved for hypertension,
now being used for the treatment of multiple
conditions, including congestive heart failure,
ness against pheochromocytom
growth by inhibiting the AKT pathway.
a56 and in the inhibition of glioblastoma
57
53
Another drug, prazosin,
55
has also shown effective-
Artemisinins, due to their antiinflammatory property, are being investigated for their possible action
against respiratory disorders in lung cancer models.
58
1.5.2 DRUG REPURPOSING AGAINST CNS DISORDERS
Drug development for diseases affecting Central Nervous System (CNS) is
one of the most extensively studied areas. Still, the failure rate of developed
drugs is comparatively higher than in other areas, with most available ones
focusing on short-term management of symptoms instead of tackling the
cause. In degenerative diseases like Alzheimer’s disease and Parkinson’s
disease (PD), the available medications focus on reliving the observable
symptoms, while the degeneration of neurons and central cells continues,
59
worsening the condition.
Also, among the drugs synthesized, the majority
fail due to their ineffective penetration across the BBB (blood–brain
barrier). They are the most significant limiting factor in successful CNS
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Drug Repurposing and Computational Drug Discovery: Strategies and Advances
drug discovery as it excludes almost 98% of the small-molecule drugs and
100% of large-molecule drugs from reaching the brain.60 Repurposing drugs
already intended for other CNS disorders have the additional benefit of
having a greater chance of crossing the BBB and more chance of success.
61
Mifepristone, approved by the FDA in 2000 as a pregnancy-terminating
agent due to its progesterone-inhibiting properties, is also known to be
an effective selective inhibitor of glucocorticoids and later discovered to
possess anticancer activity. Evidence suggests mifepristone is effective
against glioma, one of the most commonly occurring tumors in the CNS,
with minimal cytotoxicity on healthy cells.62 Studies showed increased
apoptotic activity and decreased proliferation of cancer cells using mifepristone in combination with temozolomide in glioblastoma patients.
63
Mifepristone is also found to be effective against PD (psychotic depression), which is characterized by elevated levels of cortisol, differentiating
it from other subtypes of depression. Currently, there are no FDA-approved
drugs for its treatment, and with promising Phase 2/3 results, mifepristone
could serve as a potential therapeutic agent for the treatment of PD in the
future.64 Mifepristone was repurposed to treat Cushing’s syndrome, caused
by elevated glucocorticoid levels and was approved by FDA in 2012 after
65
many clinical trials.
Amantadine, the antiviral approved for influenza,
was later repurposed for Parkinson’s based on various case studies.
Patients showed decreased tremor and akinesia and increased rigidity with
controllable side effects upon its administration.
66
Atomoxetine, initially
intended for treating Parkinson’s, was repurposed for treating ADHD
(attention-deficit hyperactivity disorder) due to its selective norepinephrine reuptake inhibition in the pre-synapses.67 Ropinirole, an agonist of
dopamine D2, initially intended for hypertension,68 was later repurposed to
treat advanced and early Parkinson’s disease.
69
Ropinirole has also shown
effectiveness against RLS (restless legs syndrome) in a 52-week study
where it was found safe for long-term use and was successful in improving
the symptoms.70 Mecamylamine was first approved for hypertension due
to its ability to block impulse transmission in the ganglia.71 Infliximab was
approved for the market in 1998 to treat CD (Crohn’s disease).72 Infliximab
is a well-established antagonist of TNF-α and was used to treat CD patients
unresponsive to conventional therapy. Increased production of TNF-α is
associated with various conditions like Parkinson’s and Alzheimer’s
diseases. It was showed that infliximab, with its TNF blocking property,
could reduce the risk of Alzheimer’s disease73 and needs to be explored
further to be of clinical use.
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1.5.3 DRUG REPURPOSING AGAINST CARDIOVASCULAR DISEASES
Cardiovascular diseases (CVDs) are the leading cause of death worldwide,
according to WHO statistics. The number has steadily increased from 2
million to 8.9 million from 2000 to 2019. Repurposing of diabetic and antiinflammatory drugs has been especially successful, as both are a significant
74
factor in many CVDs and are a promising area for repurposing.
Paclitaxel,
approved by the FDA in 1992 for the treatment of ovarian cancer, is recently
found helpful in controlling restenosis in patients who underwent coronary
intervention. Restenosis occurs due to narrowing of the lumen due to the
75
increased proliferation in the artery.
Results from various randomized trials
show paclitaxel to be effective and safe, with reduced occurrence of reste-
76
nosi
s.
PCB (paclitaxel coated balloon) angioplasty was also found effective
long term and had the potential to be developed into a first-line therapy for
restenosis.
77
Colchicine, approved for managing gout, has established anti-inamma-
tory properties through the disruption of microtubules.
78
It has been shown
effective against pericarditis and was approved in 2015 for its rst-line
treatment. Recent meta-analysis data shows reduced pericardial effusion
and recurrence risk of pericarditis.79 Currently, many trials are going on
to evaluate the effect of colchicine on other cardiovascular disorders like
STEMI (ST-segment elevation myocardial infarction), AF (atrial brillation), CAD (coronary artery disease), and percutaneous coronary intervention. Drospirenone is an oral contraceptive with anti-mineralocorticoid
activity. Meta-analysis data shows its effectiveness against hypertension in
postmenopausal women. Estrogen deciency in postmenopausal women
leads to an increased risk of cardiovascular diseases as a result of hypertension. Lowering of systolic and diastolic pressure was observed in hypertensive women with very few side effects.80 Donepezil, approved to treat
Alzheimer’s disease due to its cholinesterase-inhibiting property, was shown
to have a cardiovascular protective effect. Many PDE5is (phosphodiesterase
5 inhibitors) have cardiomyocyte heterotrophy inhibition properties and
cardioprotective effects. Sildenal, tadalal, is PDE5is initially approved for
treating erectile dysfunction but is now being investigated for their cardio
protectiveproperties.81 Currently, clinical studies are examining the effects
of sildenal on PVR (pulmonary vascular resistance) and tadalal on cardiac
stress and change of ventricular torsion.
82
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Drug Repurposing and Computational Drug Discovery: Strategies and Advances
1.5.4 DRUG REPURPOSING FOR OTHER DISEASES
Inflammatory diseases constitute a significant area of concern. They often
lead to other conditions like cancer, neurodegenerative diseases (Alzheimer’s
disease, multiple sclerosis, Parkinson’s disease, etc.), and metabolic disorders
83
(type II diabetes, obesity, etc.).
Developing therapeutic methods that can
regulate chronic inflammation can help manage these diseases to an extent.
Tosopam, an active CNS compound, was marketed for anxiety treat-
ment and had antipsychotic properties.
84
Dextosopam (enantiomer of to-
sopam) was found to be effective against IBD (inammatory bowel disease)
85
in clinical trials.
Cefadroxil, an antibiotic, targets many proteins related to
IBD like endothelin-1 receptor, alanine aminopeptidase, and peptide transporter 1, making it a promising candidate for IBD drug studies.
has anti-inammatory properties and is used in the treatment of asthma.
86
Budesonide
87
Recent studies also showed them effective against ulcerative colitis, and
88
a signicant reduction in inammation was observed.
Penicillamine was
rst approved for the treatment of Wilson’s disease and was repurposed and
approved for the treatment of RA (rheumatoid arthritis) a decade later.
89
Sirolimus, another immunosuppressive approved by the FDA in 1999, is
currently being studied for its anti-inammatory action in patients with SLE
(Systemic Lupus erythematosus) and has promising results after Phase I/
II studies.
90
Rituximab, initially approved for lymphoma, ustekinumab
approved for psoriasis, and certolizumab approved for Crohn’s disease are
some of the drugs repurposed and approved for RA in the last 10 years.
91
Infectious diseases have been an ongoing problem for centuries all around
the globe. Their ability to grow, spread, and mutate fast, along with their
increasing resistance to existing treatments and drugs, make them challenging to control. Drug repurposing became particularly important during
the outbreak of COVID-19, for which no specific treatment is available and
repurposing existing drugs was the fastest and safest solution. WHO recommended a combination therapy of the antimalarial drugs, chloroquine and
hydroxychloroquine, the HIV drugs ritonavir and lopinavir, and the antiviral
remdesivir as a method of treatment.
92
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The anticancer drug cisplatin was found to be effective against Pseudo-
monas aeruginosa. The drug was found to inhibit the endotoxin secretion
and DNA replication mechanism of the pathogen through various studies.
93
The antibiotic daptomycin, the immunosuppressant mycophenolic acid,
and the hypertensive drug manidipine are some drugs that have shown
promise against Zika virus infection.
94
The FDA-approved drug dapsone was
intended for treating leprosy but is now being studied for its antimalarial
potential.95 Studies reveal that the antibiotics Biapenem and Tabipenem,
the anti-inammatory drug ebselen, the anticancer drug bortezomib and
elesclomol, and the cardiovascular drug verapamil are effective against M.
tuberculosis infection. Bortezomib was also found effective against JEV
(Japanese encephalitis), for which no effective treatment is available. Studies
on mice models showed reduced mortality and brain damage, opening up a
new possibility of JEV treatment.
96
TABLE 1.2 List of Some Repurposed Drugs with Their Old and New Indication
clinicaltrials.gov/).
Name Old indication New indication
Amantadine Influenza Parkinson’s
Antomexetine Parkinson’s ADHD
Arbidol Antiviral COVID-19
Arsenic Syphilis Leukemia
Artemisinin Malaria Cancer, respiratory disorders
Aspirin Antipyretic, analgesic CVD, cancer
Auranofin RA Cancer
Azathioprine Immunosuppressant Rheumatoid arthritis
Biapenem Antibiotic
Bortezomib Cancer
Budesonide Asthma Ulcerative colitis
Cefadroxil Antibiotic Inflammatory bowel disease
Celecoxib Arthritis Cancer
Certolizumab Crohn’s disease Rheumatoid arthritis
Chloroquine Malaria Cancer, COVID-19
Ciclosporin Immunosuppressant Rheumatoid arthritis
Cisplatin Cancer Antibacterial
Colchicine Gout Pericarditis, STEMI, CAD
Dapsone Leprosy Malaria
M. tuberculosis infection
M. tuberculosis infection
92,68
(https://
18
TABLE 1.2 (Continued)
Name Old indication New indication
Daptomycin Antibiotic Zika virus
Disulfiram Chronic alcoholism Cancer
Donepezil Alzheimer’s disease Cardiovascular diseases
Doxycycline Antibacterial COVID-19
Drospirenone Oral contraceptive Postmenopausal hypertension
Ebselen Inflammation
Elesclomol Cancer
Favipiravir Antiviral COVID-19
Hydroxychloroquine Malaria Cancer, COVID-19
Indomethacin Anti-inflammatory Cancer
Infliximab Crohn’s disease Alzheimer’s disease
Ivermectin Antiparasitic drug COVID-19
Lopinavir HIV Zika virus
Manidipine Hypertension Zika virus
Mecamylamine Hypertension ADHD
Metformin T2DM Cancer
Mifepristone Pregnancy termination Cancer, PD, Cushing’s
Mycophenolic acid Immunosuppressant Zika virus
Nafamostat Pancreatitis COVID-19
Nelfinavir AIDS Cancer
Paclitaxel Ovarian cancer Restenosis
Penicillamine Wilson’s disease Rheumatoid arthritis
Prazosin Hypertension Cancer
Rapamycin Immunosuppressant Cancer
Remdesvir Ebola Zika virus, COVID-19
Ribavirin Hepatitis C COVID-19
Ritonavir HIV Zika virus
Rituximab Lymphoma Rheumatoid arthritis
Ropinirole Hypertension Parkinson’s disease, restless leg
Sildenafil Erectile dysfunction Pulmonary vascular resistance
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
M. tuberculosis infection
M. tuberculosis infection
syndrome
syndrome
19 Drug Discovery and Development
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TABLE 1.2 (Continued)
Name Old indication New indication
Sirolimus Immunosuppressant Systemic lupus erythematosus
Sofosbuvir Hepatitis C COVID-19
Tabipenem Antibiotic
Tadalfil Erectile dysfunction Cardiac stress
Thalidomide Pregnancy-related morning ENL, cancer
sickness
Tocilizumab Inflammation COVID-19
Tofisopam Anxiety Inflammatory bowel disease
Ustekinumab Psoriasis Rheumatoid arthritis
Verapamil Cardiovascular disease
M. tuberculosis infection
M. tuberculosis infection
The core aim of drug repurposing is to use old drugs for new indications that
are already in extensive use in cancer therapy. In the face of advantages like
validated anticancer pharmaco-kinetic properties, safety, and acceptability
in humans, yet there is still a probability of failure in late phases of clinical
trials due to the competition from efficacious new drug development. Other
obstacles in repurposed drug development include legal issues like intellectual property (IP) issue and unfair prescription charges. The IP concern stops
certain repurposed drugs from entering into the market. Filing secondary
patents offers a chance to find new targets for existing drugs. Hopefully, such
obstacles will prove resolvable.
34
Drug repurposing holds excellent promise as a reliable mode of drug
discovery. By identifying a new indication to an old drug, we can speed
up the process and provide a safe, more efficient, and economical solution to novel challenges. Also, with new investigations unraveling hitherto
unknown facts about the pathophysiology of diseases, it is necessary to
revise the mode of action of existing drugs and screen them for their potential new indications.
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