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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5649_Библиотеки_им_академика_М_И_Перельмана
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170
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
quite rare. When an off phenotype is seen, it may imply that the medicine
should be utilized more widely. A fortuitous discovery might be made
because of biological tests or experimental screenings that target certain
sickness models and drugs. When it comes to screening a broad range of
drugs or illnesses, these approaches are more adaptable. By using computational biology methodologies and bioinformatic methods, in-silico drug
screening can undertake virtual screenings of massive drug and chemical
databases. The validation steps might be examined in vitro first, and subsequently in vivo models, after the medication has been selected. This chapter
details about repurposing and computational drug discoveries in the field of
diabetes.
Diabetes mellitus (DM) is a complex metabolic syndrome characterized
1
by increased blood glucose.
Prognosis of hyperglycemia is due to reduced
insulin action or insulin secretion, loss of pancreatic β-cells causes decrease
in the secretion of insulin lead to decline in its effect in type 1 diabetes (T1D)
and insulin receptor sensitivity reduces which reduces utilization of glucose
in adipose tissue due to impairment of signaling pathway in type 2 diabetes
(T2D).2 Prevalence of diabetes reveals that more than 380 million patients
suffer from it throughout the globe, which will increase to approximately 592
3
million by 2035.
Moreover, T2D is the preliminary cause of this dramatic
rise. Sedentary lifestyles and obesity due to an increase in urbanization
contribute to the development of T2D.
Uncontrolled diabetes for a prolonged period contributes to the development of several complications associated with diabetes, such as microvascular complications (diabetic retinopathy, neuropathy, and nephropathy)
and macrovascular complications (peripheral arterial disease, coronary
artery disease, and stroke).
4
Chronic hyperglycemic conditions alter the
cellular functions and thereby lead to damage to the tissues due to alteration in the status of reactive oxygen species, advanced glycation products,
and aldose reductase. These changes in marker levels have a direct toxic
effect on several body tissues. Moreover, metabolic products of glucose
also alter the cell signaling pathways, such as the activation of protein
kinase C, which causes damage to microvascular tissues.5 These changes
in microvasculature develop atherosclerosis, which causes several chronic
complications.
171 Drug Repurposing and Computational Drug Discovery for Diabetes
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Management of diabetes clinically has been achieved by regulating glucose
metabolism in a number of ways to achieve a low blood sugar level using
several conventional drugs, which include insulin and oral hypoglycemic
agents such as sulfonylureas, bigunides, thiazolidinediones, α glucosesidase
6
inhibitors, DPP4 inhibitors, and amylin analogues.
These drugs, either
by monotherapy or combination therapy, control glucose levels within the
normal range. The systemic safety of antidiabetic agents gained attention
due to a report by the United States Food and Drug Administration (FDA)
7
on concomitant cardiovascular outcomes
.
Optimal use of these hypoglycemic agents causes weight gain and a
reduction in therapeutic efcacy. The most common side effect is hypogly-
8
cemia.
Therapeutic efcacy of conventional drugs occurs due to reduced
permeability, solubility, and lack of target specicity and an increase in drug
metabolism.9 However, conventionally available antidiabetic drugs show a
promising role in controlling blood sugar levels, but there are still some major
challenges for effective glycemic control by optimizing available therapies
and reducing the complications associated with chronic antidiabetic drug
use. There are several complications associated with each antidiabetic agent
associated with chronic use of these drugs, which are given in Table 8.1.
8.2.1 SULFONYLUREAS
Sulfonylurea agents have also been called secretagogues agents, which
10
stimulate the β-cells to secrete insulin.
Hypoglycemia is a major complication associated with the use of the sulfonylurea class of drugs in nephropathic, hepatic failure, malnourished, and elderly patients. Weight gain is
another side effect commonly observed with these drugs. From the initiation of therapy to one year, weight gain is approximately 2 kg observed in
11
patients taking sulfonylureas.
US-FDA warns the use of sulfonylureas as it
enhances the risk of cardiovascular-associated death. Literature reveals that
the use of the first generation of sulfonylurea tolbutamide enhances the risk
of cardiovascular death more than placebo and insulin do.
12
8.2.2 MEGLITINIDES
Repaglinide and nateglinide are meglitinide analogues used to treat T2D.
They increase insulin secretion by antagonizing KATP channels.
clinical trials reveal that the use of meglitinide is reported to enhance weight
13
Several
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
gain by up to 2.1 g. Meglitinides are reported to have mild hypoglycemia as
a common side effect, which also shows a lack of long-term cardiovascular
outcomes.
14
8.2.3 BIGUANIDES
Biguanides are an insulin sensitizer, that is, metformin approved for the
management of T2D. Clearance of these drugs decreases in pathological
conditions including dehydration, sepsis, congestive heart failure, renal
and hepatic impairment, which enhances the risk of development of lactic
acidosis. Metformin improves body weight even when combined with
sulfonylurea. Congestive heart failure is not commonly observed with the
long-term use of metformin, and it is one of the safest antidiabetic drugs.
15
8.2.4 THIAZOLIDINEDIONES
Thiazolidinediones (TZD; pioglitazone and rosiglitazone) are insulin
sensitizers that act as peroxisome proliferator–activated receptor (PPAR-)
agonists. They are approved for the treatment of T2D. Thiazolidinediones
are known to cause fluid retention and weight gain causes edema. Literature
reveals that TZD in combination with insulin enhances weight gain by up to
5 g after 2 years of drug treatment. Strong evidence reveals that TZD appears
to cause health failure as a side effect, and thus most drugs in this category
are banned for clinical use.
16
8.2.5 α-GLUCOSIDASE INHIBITOR
α-Glucosidase inhibitors (voglibose, acarbose, and meglitinide) inhibit the
enzyme α-glucose hydroxylase and α-amylase enzyme, which contribute
to the conversion of polysaccharide carbohydrates into monosaccharides.
The most serious problem associated with the use of these drugs is diabetic
ketoacidosis; however, this class of drug commonly metabolizes in the
GI track by gastrointestinal enzymes and absorbs the least amount in the
systemic circulation. Thus, the risk of weight gain and hypoglycemia was
not observed with the use of α-glucosidase inhibitors. Moreover, there was
a reduction in the risk of the development of congestive heart failure and
hypertension of up to 49% observed with the use of these agents.
17
173 Drug Repurposing and Computational Drug Discovery for Diabetes
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8.2.6 GLUCAGON-LIKE PEPTIDE 1 (GLP-1) REGULATORS
Postprandial glucose homeostasis is regulated by GLP-1 in response to
ingested nutrients. In systemic circulation, DPP-4 inhibits GLP-1 into
an inactive metabolite. Thus, there are two different categories. GLP-1
receptor agonists and DPP-4 inhibitors were developed. DPP-4 inhibitors
(Sitagliptin) are reported to act neutral on weight gain, and GLP-1 agonists
reduce weight gain by more than 2 kg. GLP-1 receptor agonists have some
role in pancreatitis, but an exact relationship has not been developed yet. It
is also contraindicated in patients with thyroid cancer or a family history of
it, as the GLP-1 agonist stimulates the proliferation of type C cells. DPP-4
expression has been found in T cells, suggesting that DPP-4 inhibitors may
modulate T cells and have an immunomodulatory effect.
18
8.2.7 SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS
Sodium-glucose transporter 2 (SGLT2) inhibitors modulate renal glucose
handling and thereby lower the glucose level. SGLT2 inhibitors are
contraindicated in patients with renal failure and hepatic insufficiency. Its
consumption for more than 12 months reduces weight and fluid in the body
and induces hypotension in the patient. Moreover, SGLT-2 also reported to
modulate the level of lipoprotein, and thus its effect on cardiac complications
needs to be studied in a detailed manner.
19
Safety Consideration and Common Side Effects of Antidiabetic Agents.
Antidiabetic agents Hyperglycemia Weight Contraindication
Sulfonylurea drugs Ye s Increases –
Metformin/bigunides No Mildly
decreases
TZDs No Increases Heart failure and
α-Glucosidase
inhibitors
GLP-1 receptor
agonist
DPP-4 inhibitors No Neutral Pancreatitis history
Amylin analog Ye s Initially
SGLT-2 inhibitors No Neutral Renal failure
No Decreases Renal failure, liver cirrhosis,
No Decreases Pancreatitis, renal failure,
decreases
Metabolic acidosis, hepatic
failure, and renal failure
hepatocellular diseases
and intestinal disease
endocrine neoplasia
Gastroparesis
174
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
Diabetes-associated morbidity and mortality occurs due to cardiovascular
disease. Previously, there was no specific need for novel therapy for the
management of T2D because existing therapies did not have any issues
20
with cardiovascular safety.
However, a meta-analysis published in 2007
reveals the greater chances of stroke and myocardial infraction in patients
treated with rosiglitazone than control.
21
Thereafter, this class of drug was
completely withdrawn from the market for clinical use. The FDA changed
the drug safety guidance related to therapies for T2D so that there is no
cardiovascular risk associated with new drugs for the management of it.
These regulations state that relative risk should be <1.8 and participants
included in the study with diabetes (advanced age, renal impairment, and
chronic diabetic) should be included in the study. The study also includes
at least two years of safety data; stroke, myocardial infarction, and cardiovascular mortality should be included in the study. Meta-analysis will be
performed for the unacceptable cardiovascular risk from the data of phase
II and III clinical trials.
22
Presently, drugs available under development
for T2D need to follow these FDA guidelines, which require patients with
cardiovascular disorders to enroll in trials, and it requires longer and larger
trials. This all contributes to greater expense and delays the time for the
drug to come to the market.
T2D is a multifactorial disease in which several pathogenic pathways are
involved in dysregulation of glycemic control. Oxidative stress, systemic and
23
tissue-specic inammation, and altered lipid metabolism
are all factors
to consider. These pathogeneses are involved in the development of other
diseases too, and drugs used for the management of those diseases that act on
a given pathogenic pathway could be promising therapies for treating T2D.
DRUG DISCOVERY
Pharmaceutical research and industry have been paying close attention to
the possibility of repurposing existing pharmaceuticals and producing novel
drugs, as well as the efficiency of repurposing over conventional de novo
drug development methods. Repositioning, reprofiling, redirection, retaking,
and therapeutic switching are all examples of drug repurposing (Fig. 8.1).
175 Drug Repurposing and Computational Drug Discovery for Diabetes
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Traditional studies on repurposing usually focused on identication
of novel indications for drugs based on similarity of its mode of action.
Conventional drugs target on new targets based on some characteristics like
drug–disease relationship, drug side effects, and its chemical structures.
In general, there are two basic drug repositioning principles. First,
because of the interdependence of various disorders, medications developed
for one disease may also be effective for other diseases. Second, because
medications are inherently confusing, they can be linked to a variety of
targets and pathways.
In the next several decades, the number of individuals suffering from
diabetes will climb substantially. As a chronic metabolic disease, T2D
is characterized by insulin resistance and elevated blood sugar in most
sufferers. Several underlying factors contribute to poor glycemic control in
T2D, which is a complex condition. There has been a reconsideration of T2D
therapy options that target comparable pathophysiological systems because
of their adaptability.
When it comes to drug research, the creation of new medications and
agents demands a signicant investment of time and money. Repurposing
or repositioning medicine has become more popular in the past 30 years due
to a decrease in the number of FDA-approved pharmaceuticals. New drug
development is a time-consuming and costly undertaking that is character-
ized by a signicant degree of uncertainty about whether a medicine will
succeed. Due to rising costs and time constraints, these gains have not been
able to be translated into therapeutic improvements as quickly as planned.
There are several methods to repurpose medications that have previously
been approved by the FDA and/or are currently under research. It is a new
technique that offers cheaper research costs and acceptable safety proles
since much of the trial data is already available in the public domain.
Because the medicine has already undergone clinical testing, the chance
of failure is almost nonexistent or very low. Due to extensive testing and
safety evaluations previously completed, the time required to produce a
new medicine is greatly reduced. Third, the medications that are currently
on the market need relatively little investment. At this time, validation of
targets and studies for on- and off-target drug repositioning have become
natural allies in chemical biology. Repurposing drugs requires three primary
phases before they can be tested in phase II clinical trials: Identication of
the proper drug, rigorous study of the drug’s action in clinical models, and
appraisal of its utility.
176
Different approaches for drug repurposing.
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
Some of the present ways for applying drug-repurposing technology are
targeted mechanism-based, pathway or network-based, signature-based,
target-based, knowledge-based, and blind-based.24 The above-mentioned
medication repurposing strategies were successful in both clinical and
preclinical research to nd the drug’s new role in treating DM.
8.4.1 PROTEINS/PATHWAYS TARGETED APPROACH
Diabetic mellitus (DM) is the most prevalent metabolic disorder, and insulin
insufficiency, inappropriate insulin usage, or both, may cause blood glucose
levels to vary. An autoimmune attack on pancreatic islet cells causes type 1
diabetes; insulin signaling issues and environmental factors are to blame for
T2D. The glucose metabolism of DM patients has recently been successfully
controlled by glucagon-like peptide-1 (GLP-1) receptor agonists and DPP-4
inhibitors, in addition to insulin, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, sulfonylureas, and biguanides. Incretin hormones,
including glucose-dependent insulinotropic peptide (GIP), are degraded by
the DPP-4 enzyme, which is inhibited by DPP-4 inhibitors. Chemokines and
growth factors are also destroyed by DPP-4, suggesting that DPP-4 inhibitors may help regulate inflammatory conditions. Incretin hormones increase
insulin secretion and glucagon release, and they also lower beta cell mortality.
It is not uncommon for patients on FDA-approved DPP-4 inhibitors like sitagliptin, vildagliptin, alogliptin, and saxgliptin to have pancreatitis, hepatitis,
or renal damage. Over the course of therapy, complications such as diabetic
177 Drug Repurposing and Computational Drug Discovery for Diabetes
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retinopathy and painful diabetic nephropathy have been recorded, and they
are more frequent in insulin-dependent diabetes patients.
Incretin effect regulates the blood glucose levels by enhancing secretion
of insulin and controls the release of glucagon, which reduces the mortality
of β-cells too. Patients on DPP-4 inhibitors are commonly associated with
pancreatitis, hepatitis, or renal damage. Painful diabetic nephropathy and
diabetic retinopathy are more frequent in insulin-dependent diabetes patient.
Diabetic nephropathy is a painful condition that may be treated with
opioids, tapentadol, and lidocaine. Studies in both clinical and preclinical
settings have shown that combination treatment for DM is benecial. There
has been evidence in clinical studies that NSAIDs may reduce the cyclooxygenase (COX) enzymes. However, several of these therapies have the
potential to cause renal failure, and hence, NSAIDs are typically avoided in
the treatment of diabetic mellitus. There is evidence that arthritis medications such as salsalate and ibuprofen, which are often prescribed to people
with T2D, might reduce blood glucose levels by decreasing inammatory
mediators, suggesting that NSAIDs alone may be successful in doing so.
In both clinical and preclinical trials, combination treatments for diabetes
have been demonstrated to be successful. Salicylate, a pain-relieving medicine that already existed, was acetylated to make aspirin, which is the most
popular and well-known drug in the world at the time. Salicylate improves
25,26
glycemia and lowers inammatory mediators in T2Dm.
Salicylate and
the cellular senescence of IKK-b in the skeletal muscle restrict fat-induced
insulin resistance, which means that fat-induced changes in insulin signaling
activity could be a new class of T2D medicines.
27
In a recent trial, HIV-1 and hepatitis B infections were originally treated
with the anti-inammatory drug known as nucleoside reverse transcriptase
inhibitors (NRTIs). Preliminary studies in the C57BL/6J mouse model show
that it enhances insulin sensitivity and slows the evolution of T2D.28 Chen
et al. found that the antidepressant medicine doxepin activates FAM3A
signal transduction pathways in the hepatic and brown fatty tissue to
ameliorate hyperglycemia and steatosis in diabetic mice. Doxepin may be
preferentially suggested as an antidepressant in the treatment of people with
diabetes who also have depression.
29
Telmisartan reduced obesity-induced
insulin resistance, according to Liu et al., via suppressing ER stress through
AMPK activation.30 Similarly, multiple studies suggest that an existing class
of drugs might be repurposed for the prevention of diabetes. Niclosamide
ethanolamine (NEN) is an FDA-approved anthelmintic drug for the treatment of parasitic worms. A recent study by Tao et al. showed the potential
178
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
of NEN as a therapeutic and management tool for people with T2D. Mice
treated with NEN had better energy distribution and lipid metabolism.31 It
is a signicant medical disorder known as diabetic kidney disease (DKD).
There is a pressing need for new therapies to prevent or delay the progression
of DKD. Many biological processes, such as cell viability and mortality, are
regulated by potassium channel KCa3.1. The development and course of
DKD are inuenced by mitochondrial dysfunction. Inammation, proliferation, and activation of cells are all linked to mitochondrial dysfunction and
KCa3.1 dysregulation. Recently, it has been shown that KCa3.1 absence
improves the mitochondrial dysfunction associated with DKD by regulating
abnormal mitochondrial dynamics and rectifying decient BNIP3-mediated
mitophagy, which is attributed to the modication of mitochondrial quality
control. DKD may benet from pharmacological reduction of KCa3.1’s
involvement in brosis, inammation, and mitochondrial dysfunction, which
might lead to a new treatment option. Because of its high level of safety,
repurposing senicapoc might have a positive impact on human health.
32
8.4.2 TRADITIONAL MEDICINES-BASED APPROACH
While great attention has been made on repurposing current pharmaceuticals to cure/manage illnesses, traditional medicines are an alternative and
maybe neglected source of novel antidiabetic molecules. For hundreds of
years, various pathological conditions have been treated with the use of
these formulations and extracts. In the case of T2D, this prolonged history
of use often provides strong empirical information for their advantages on
glucoregulatory mechanisms as well as the absence of serious side effects.
Furthermore, observations with an ancient herbal medicine led to the
development of antidiabetic guanidine pharmaceuticals like metformin. It
was discovered that guanidines in Galega officinalis, a plant that produces
the chemical, might improve the symptoms of diabetes, including frequent
33
urination.
Moving further with conventional medications requires identifying the active ingredients in these formulations. There are thousands of
instances of traditional medicines being used to successfully find possible
antidiabetic molecules. Berberine is a phytoconstituent that was first tested
to treat viral diarrhea.
34
Cortidisrhizoma and Cortex phellodendri are richer
in berberine content which possesses insulin-sensitizing and insulinotropic
35
activities through the activation of AMPK.
Bitter melon (Momordica
charantia) extracts have been used in traditional medicine to treat diabetes
symptoms for many years, but the active ingredient has remained a mystery.
179 Drug Repurposing and Computational Drug Discovery for Diabetes
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8.4.3 SIDE EFFECTS AND ADVERSE DRUG EVENT-BASED APPROACH
Documentation on the treatment of illnesses that arise in rodents is also
utilized to repurpose drugs in humans because of the general parallels in
targets. Side effects are common in drug regimens for specific disorders.
Drug repurposing may also be triggered by clinical findings of unexpected
adverse effects reported by patients or by clinicians’ experiences of unexpected conditions cured by drugs. Although some side effects are considered
infrequent, they are nevertheless implicated in the pathophysiology of a
disease. Indeed, they may reveal a severe phenotype. Many associations
include explicit repurposing theories, such as hypoglycemic medicines being
possible diabetes candidates. Drugs that identify porphyria as a side effect,
according to drug repositioning based on the side effect, may serve as antidia-
36
betics. Porphyria is a genetic disease that affects only a few people.
Patients
with this hereditary condition have a lower risk of developing porphyria
when they become diabetic.
37
Antidiabetic medicines have been linked to an
increased risk of developing porphyria. A subgroup of the population having
a hereditary porphyria may conceivably be used as a “model” for assessing
antidiabetic medications with porphyria as the goal. Consequently, a drug
that produces porphyria in this subset with the genetic variation might be
an effective therapy for diabetes in a wider population. As a result, a drug’s
off-phenotype in a subpopulation may indicate that it should be used in a
larger population. Lithner et al. had reported in the study of 16 patients who
developed diabetes in a study of 328 Swedish porphyria patients all had their
38
porphyria symptoms alleviated.
Porphyria is a known side effect of the
drugs valproic acid, pyrazinamide, naproxen, and estradiol; nevertheless,
diabetic doctors do not suggest them because of the risk of developing the
disease.
38
Valproic acid, an anticonvulsant, has been demonstrated to lower
blood sugar levels in Wfs1 mutant mice in latest research.39 Pyrazinamide is
an anti-TB medicine, and T2D is a well-known risk factor for tuberculosis.
40
In prediabetic mice, naproxen has been demonstrated to delay or prevent the
development of T2D from occurring.
39
8.4.4 COMPUTATIONAL APPROACHES AND TECHNIQUES (FOR
ANTIDIABETIC DRUG DISCOVERY)
Traditional techniques used for drug discovery have several limitations like
time consuming and costly, and thus drug repurposing based on computer
technologies is an option for pharmaceutical industry.
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