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140
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
The computational approach of drug repurposing is also known as “in silico
drug repurposing,” which belongs to the field of computational pharmacology.
This approach is classified into two parts – the first being the discovery of
new indications for an existing drug (drug centric) and the second one is the
identification of effective drugs for a disease (disease centric).
for the failure or success of drug development. Therefore, in silico techniques
have been widely recognized and the drug absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties are being considered at an
early stage to reduce failure rates in the clinical phase of drug discovery. Some
important tools and techniques used during in silico approaches are as follows:
• Molecular modeling: Molecular modeling focuses on predicting the
strength of the interaction between a potent molecule and a transporter
or metabolic enzyme.
• QSAR: It is used for the prediction of the pharmacokinetic properties
relying mainly on traditional models or constructed data sets developed using the software.
• PBPK: It has been used to predict pharmacokinetics by using some
software programs.
• ADMET: ADMET properties play a significant role and can be
predicted using online software.
• Molecular docking: It focuses on the physical interactions between
plausible drugs and their specific targets. Here, the chemical and
physical binding of drugs to the protein of interest is studied.
• MD simulations: MD simulation represents a proper way to study atomic-
level information about binding of ligands to targeted proteins. On the
basis of MD trajectories, the root-mean-square deviation (RMSD), rootmean-square fluctuation (RMSF), the radius of gyration (Rg), number of
hydrogen bonds and binding free energy of the complexes are predicted
to analyze and get insight into their structural stabilities, binding modes,
and binding strengths of the designed drug candidates.
30,31
Many invaluable advantages such as reduction in drug development cost,
easy availability of drug components, higher success rates, and acceleration
141
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of the drug development process have been observed by integration or adoption of drug repositioning. Repurposed drugs are already toxicologically
assessed and consideration of all safety measurements reduces the chances
of failure to a great extent. Known drugs with new targets or those with
known mechanisms for new indications are considered in the repurposing or
repositioning of drugs.
32
Drug companies have lots of advantages with drug repositioning because
new drug synthesis using conventional technology is a time-consuming
33
process.
However, the high rate of drug failure of newly synthesized drugs
causes a major reason for using the repositioning strategy. A new drug can be
obtained by better treatment options with comparatively low cost as well as
a low time consumption period.
34–37
Many scientists are working to nd out
the alternative uses of generic or approved drugs for human welfare world-
Table 6.2 represents the drug repurposing target in many inammatory
wide.
mediators.
TABLE 6.2 Repositioned Drugs in Inflammatory Diseases Targeting Inflammatory
Mediators.
Sl.
Drug Inflammatory mediator Disease
No.
1 Simvastatin IL-1, IL-6, IL-8, IL-12, CD4 T-cell, Th2,
ICAM-1, and VCAM-1
2 Mangiferin Nrf2 expression; IL-1 and IL-18; and
NLRP3
3
A. apiacea Hance
4 Rapamycin mTOR, IL-13, and IgE Asthma
5 Heparin iNOS, II-4, ARG1, and ARG2 Asthma
6 Rifampicin Histamine, b-HEX, PGD2,
7 Methylthiouracil TLR2, TLR4, RAGE, and p38, NF-κB Sepsis
b-HEX, b-N acetylhexosaminidase Hexosaminidase A; ARG1, arginase 1; ARG2, arginase
2; ICAM-1, intercellular adhesion molecule 1; IgE, immunoglobin E; iNOS, inducible nitric
oxide synthase; IL, interleukin; mTOR, mammalian target of rapamycin; NF-κB, nuclear
factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2
(NFE2)-related factor 2; p38, protein kinase 38; PGD2, prostaglandin D2; RAGE, receptor
for advanced glycation end products; TLR2, toll-like receptor 2; TLR4, toll-like receptor 4;
TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion protein 1.
IκIBs, NF-κB p65, p38, RANTES, IL-8,
IL-6, and TARC
proinflammatory cytokines, TNF-α, and
COX-2
Sepsis and asthma
Sepsis
AD
AD
142
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
For characterization as well as dening the drug activity, zebrash pres-
ents a valuable platform. Larvae and embryos of zebrash are used in the
bioassay of drug discovery.
38
Table 6.3 represents the considerable top 12
hits of zebrash using anti-inammatory screening.
S. Drug name Generic name Therapeutic group Mechanism of
No. action
1 Amodiaquine Amdaaquin, amobin, Antimalarial Heme polymerase
amochin, basoquin, inhibitor
trimalact, camoquine,
larimal
2 Etodolac Etodol, etodolac, Anti-inflammatory COX inhibitor
apeotex, ETOFACT, (NSAIDs)
etogesic
3 Pinacidil Pindac Vasodilator K
Mafenide Sulfamylon, abamide, Antibacterial Inhibitors of folic
hydrochloride emilene, homonal acid biosynthesis
malfamin, marfanil
4 Clonidine Clonidine, mylan, Antihypertensive Alpha 2
hydrochloride
5 Acetohexamide Dymelor Antidiabetic Blocks
6 Fludrocortisone Flrinef, astoni-h, Mineralocorticoid Causes kidneys to
acetate
7 Niflumic acid Donalgin, flogovital, Anti-inflammatory COX inhibitor
8 Methyldopa Aldomet, aldochlor, Antihypertensive L-aromatic amino
clonidural, cloniprex antagonist/
clonistada, clonnirit, imidazoline
clophelin agonist
(type-II non-insulin ATP-sensitive K
dependent) plus channels/
cortineff, florineff retain sodium
acetate, astonin, merk,
lonikan
forenal, niflactol, niflam,
landdruma
aldopren, aldotensin, acid
alfametildopa,
datleal, dopagrand inhibitor
(NSAIDs)
+
channel
Ca2+activator
stimulates insulin
release
Decarboxylase
TABLE 6.3 (Continued)
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S.
Drug name Generic name Therapeutic group Mechanism of
No.
9 Nefopam
hydrochloride
10 Alfuzosin
hydrochloride
11 Chlorphenesin
carbamate
12 Etodolac Etodol, etodolac,
NSAIDs: non-steroidal anti-inflammatory drugs.
Acupainlex, acupain,
acuten, anton, benoton,
glosic, ketopen, licopam,
neforex, paton, sezen,
tonfupin, xripa
Uroxatral, rilif, tevax,
unibenestan, urion,
uroXatral OD, weiping,
xatger, zofu
Cloricool, kalsont,
maolate, muslax rinlaxer,
skenesin, steacol
apeotex, ETOFACT,
etogesic
Analgesic Unknown
Antihypertensive Alpha
Muscle relaxant Blocks nerve
Anti-inflammatory
(NSAIDs)
action
1-adrenergic
antagonist
impulses
COX inhibitor
143
Increasing interest in drug repositioning has been developed due to the
sustained high failure rates and costs required to bring new drugs to market.
In the case of anti-inflammatory drugs, the risk is amplified by the looming
threat of drug resistance and the pressing need for flawless strategies to
tackle the problem. Indeed, in all likelihood, it requires a widespread effort
from public-private partnerships, non-profit groups, academic researchers,
and companies to successfully investigate and approve drugs for other indications. Academic laboratories and small biotech companies have frequently
discovered new activities for existing drugs, but the translation of these
discoveries to the clinic requires additional sophistication available with
large pharmaceutical companies. There was hope that led discovery based
on drug repurposing could deliver the next generation of anti-inflammatory
agents. Indeed, new momentum is emerging from government-led initiatives
such as the NIH program, the National Center for Advancing Translational
Science, and more recently, the Medical Research Council in the United
Kingdom has invested in this area. Overall, these initiatives lend credence
144
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
to the potential of drug repurposing and should encourage repurposing in
academia and large pharmaceutical companies alike.
KEYWORDS
• drug repurposing
• drug resistance
• antibiotics
•
• synergistic
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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 Cardiovascular
Disorders
JOHRA KHAN
1
1,2
and MITHUN RUDRAPAL
3
2
3
ABSTRACT
The recent reports on developments in pharmaceutical research shows a
decline in success of new pharmaceutical compounds in market last ten years
due to which the time of new drug development also increased from 9 to 14
years. Drug repurposing is a method to use old drugs by repositioning them,
which can reduce the new drug development time and cost. Drug repurposing
also helps in predicting new therapeutic potentials of old drugs approved by
FDA. Some of the commonly repurposed drugs are: metformin designed for
diabetes type 2, now repurposed for cancer therapeutic and under clinical
trial phase III, sildenafil and thalidomide designed for sickness and angina
now repurposed for leprosy and erectile dysfunction. Due to limited data
availability on cardiovascular profile of anti-inflammatory drugs the use of
148
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
these drugs are limited. Drug repurposing is a great tool to identify safety of
different drugs in CVD condition. The data of different studies available till
now shows possibility of monoclonal antibodies as target therapy for CVDs
in coming years. Data of anti-inflammatory drugs like colchicine that have
been repurposed for CVDs shows promising results in patients of STEMI.
Similarly Metformin, an anti-diabetic drug also shows effective inflammatory process control and cardioprotective properties. The future studies need
more evidences from clinical trials to better repurpose these drugs and their
approval to be used in CVDs.
The recent reports on developments in pharmaceutical research show a
decline in the success of new pharmaceutical compounds in market in the
last ten years due to which the time of new drug development also increased
1
from 9 to 14 years.
Drug repurposing is a method to use old drugs by
repositioning them, which can reduce the new drug development time and
cost.2 Drug repurposing also helps in predicting new therapeutic potentials
of old drugs approved by FDA. Some of the commonly repurposed drugs
are: Metformin designed for diabetes type 2, now repurposed for cancer
therapeutic and under clinical trial phase III, Sildenafil and thalidomide were
designed for sickness and angina now repurposed for leprosy and erectile
dysfunction.
3
7.1.1 CARDIOVASCULAR DISORDERS AND ITS CLASSIFICATION
Cardiovascular disorders (CVDs) are a cluster of diseases including injuries
4
that affect heart and blood vessels or cardiovascular system.
The risk of
cardiovascular disease increases with age and most cardiologists believe
that after 35 years of age if any risk related to CVDs present confirms the
4–5
beginning of CVDs already begins.
CVDs are one of the leading causes of
deaths around the world. The global burden of cardiovascular disease is on
rise, especially in high-income countries at an alarming rate during the last
decade.6 The prevalence of CVDs increased from 257 million to 285 million
in the last five years and the total death increased from 12.1 million to 19.7
million in the last decade.
7
CVDs are classied on the basis of cardiovascular system affected. Some
of the types are congenital heart disease, peripheral arterial disease, coronary
149 Drug Discovery for Cardiovascular Disorders
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heart disease, aortic aneurysm, angina, stroke, rheumatic heart disease,
congenital heart disease, deep vein thrombosis, and many others less known
8
forms.
Congenital heart disease (CHD), also referred to as atherosclerotic heart
and coronary artery disease, occurs due to deposition of atheromatous
plaque in arteries supplying blood to myocardium.
9
The symptoms of CHD
occur in the last state of disease and in most cases it remains silent and
sudden heart attack only reveals its presence and ruptured plaque causes
blockage in blood ow resulting in sudden death.10 Peripheral arterial
disease is caused by blockage due to fatty material built up in peripheral
arterial supplying blood to legs. These blockages further narrow the arteries
supplying blood to heart causing angina or sudden heart attack.
11
If the
peripheral arteries to the neck also get affected, it affects the blood ow to
12
brain causing stroke.
Congenital heart disease represents a group of abnormalities including structural and functional abnormalities in heart present
before birth due to developmental errors or genetic disorder
s.13 Coarctation
of aorta is also congenital heart diseases that remain silent without causing
any complications in the form of a small ventricular septal defect.
14
Some
of the congenital heart diseases can be treated with medicine while for some
9
it needs surgeries.
Due to development in medical technologies and recent
surgery techniques the death rate due to congenital heart disease reduced to
5% in comparison with the 1970s data recorded which was 30%.
15
FIGURE 7.1 Different types of cardiovascular diseases.
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