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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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80
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
target proteins that are involved in a disease pathway (proteomics), specific
genomic data associated with a disease (genomics), and metabolic pathways
of a disease (metabolomics) are taken into consideration for disease-based
30
drug repurposing.
A flow chart of the drug repurposing process is given in
Figure 4.1. Some examples of drugs that have been repurposed for parasitic
diseases and NTDs are given in Tables 4.1 and 4.2, respectively.
TABLE 4.1 Repurposed Drugs for Parasitic Diseases.
Drug Original use New indication Possible References
mechanism
against newly
indicated disease
Idelalisib Anticancer Malaria
Regorafenib Anticancer
Bleomycin Anticancer
Roxithromycin Antibiotic
Erythromycin Antibiotic Inhibition of [31]
Inhibition of [31]
plasmodium
enzymes such as
kinases
Inhibition of [31]
plasmodium
enzymes such as
kinases
Induction of [31]
oxidative stress
by producing free
radicals
Inhibition of [31]
essential enzymes
essential enzymes
Drug Original use New indication Possible References
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mechanism
against newly
indicated disease
Prochlorperazine Antipsychotic Dengue Inhibits viral
[32]
binding and viral
entry
Quinine Antimalarial Inhibits viral
[33]
protein synthesis,
induces
production of
viral genes
for improved
immunity against
dengue infection
Minocycline Antibiotic Inhibition of viral
[34]
protein synthesis,
and upregulation
of antiviral genes
Metoclopramide Antiemetic Inhibition of viral
[35]
replication
Memantine
Anti-Alzheimer Chikungunya
–
[36]
hydrochloride
Novobiocin Antibiotic Inhibition of viral
[37]
replication by
inhibiting nsP2
protease
Telmisartan Antihypertensive Inhibition of viral
[37]
replication by
inhibiting nsP2
protease
Suramin Antiparasitic Inhibition of
[38]
cellular entry
81 Parasitic Diseases and Neglected Tropical Diseases (NTDs)
Fluconazole Antifungal Leishmaniasis Inhibition of
lanosterol-14-α-
demethylase
Itroconazole Antifungal Inhibition of
lanosterol-14-α-
demethylase
[39]
[39]
82
Drug Original use New indication Possible References
Ketoconazole
Amphotericin B
Posaconazole
Chloroquine
Niclosamide
Suramin
Nitazoxanide
Imatinib
Artemether
Artesunate
Dihydroartemisinin
Nilutamide
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
mechanism
against newly
indicated disease
Antifungal
Antifungal
Antifungal
Antimalarial
Anthelmintic
African-sleeping
sickness
Antiprotozoal
Anticancer
Antimalarial
Antimalarial
Antimalarial
Anticancer
Zika virus
Soil-transmitted
helminths
Inhibition of
lanosterol-14-α-
demethylase
Inhibition of
lanosterol-14-α-
demethylase
Inhibition of
lanosterol-14-α-
demethylase
Inhibition of viral
protein synthesis,
or inhibition of
cellular entry
Inhibition of
essential enzymes
such as kinases
Inhibition of viral
protein synthesis
Inhibition of viral
replication
–
–
–
–
–
[39]
[39]
[39]
[40]
[40]
[40]
[40]
[41]
[41]
[41]
[41]
[41]
TABLE 4.2 Repurposed Drugs for NTDs.
Drug Original use New indication Possible mechanism
against newly
indicated disease
Rifampin Used in
combination
therapy for
tuberculosis
Buruli ulcer Interferes with
β-subunit of bacterial
RNA-polymerase and
prevents the synthesis
of RNA
References
[42]
83 Parasitic Diseases and Neglected Tropical Diseases (NTDs)
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Drug Original use New indication Possible mechanism References
against newly
indicated disease
Streptomycin Antitubercular Binds to 30s subunit
[43]
of the bacterial
ribosome and inhibit
protein synthesis
Clarithromycin Antibiotic Inhibits polypeptide
[44]
synthesis by binding
with 23S rRNA
on 50S ribosomal
subunit leading to a
bacteriostatic effect
Sparfloxacin Antibacterial Interfere with DNA
[45]
replication and
transcription by
inhibiting bacterial
DNA gyrase enzyme
Clofazimine Antileprotic Reduced to a reactive
[46]
oxygen species by
mycobacterial type
2 NADH:quinone
oxidoreductase
causing toxic effects
to the bacteria
Clomipramine Antidepressant Chagas disease Irreversible inhibition
[47]
of trypanothione
reductase
Thioridazine Antipsychotic Irreversible inhibition
[48]
of trypanothione
reductase
Ketoconazole Antifungal Impairment in the
[49]
function of cytochrome
P-450 sterol 14 alphademethylase, retarding
parasitic growth
Itraconazole Antifungal Impairment in the
[49]
function of cytochrome
P-450 sterol 14 alphademethylase, retarding
parasitic growth
84
TABLE 4.2 (Continued)
Drug Original use New indication Possible mechanism References
Fluconazole Antifungal Impairment in [49]
Artesunate and Antimalarial Fascioliasis Disruption of [50]
artemether spermatogenesis
Bithionol Anthelminthic Poorly understood, [51]
Emetine Amebicidal Disrupts protein [52]
Praziquantel Anthelmintic Activates a transient [53]
Metronidazole Antibiotic Distortion of the [54]
Eflornithine Anticancer Human African Retards cell [55]
Nifurtimox Chagas disease Generation of [56]
Pafuramidine Pneumocystis Interrupts with DNA [57]
Rifampin Antitubercular
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
against newly
indicated disease
the function of
cytochrome P-450
sterol 14 alphademethylase,
retarding parasitic
growth
causes morphological
changes
synthesis
receptor potential
melastatin ion
channel leading
to paralysis of the
parasite
helical structure of
the DNA
trypanosomiasis proliferation by
inhibiting ornithine
decarboxylase which
in turn depletes
putrescine and
spermidine
reactive oxygen
species causes
detrimental effects
to the cellular
components
pneumonia synthesis
Onchocerciasis
Inhibits RNA [58]
synthesis
TABLE 4.2 (Continued)
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85 Parasitic Diseases and Neglected Tropical Diseases (NTDs)
Drug Original use New indication Possible mechanism
against newly
indicated disease
Ivermectin Antiparasitic Increases the influx
of chloride ions by
glutamate-gated
chloride channels
as a consequence
dysfunction of the
excretory pore, flaccid
paralysis, and death of
the parasite takes place
Moxidectin Anthelmintic
(for animals)
Increases the influx
of chloride ions by
glutamate-gated
chloride channels
as a consequence
dysfunction of the
excretory pore, flaccid
paralysis, and death of
the parasite takes place
Emodepside Anthelmintic Interacts with
calcium-gated and
potassium-gated
voltage channels
Albendazole Anthelmintic Prevents microtubule
elongation which
interferes with
chromosome
segregation and cell
division ultimately
leading to defective
embryogenesis
Rifampicin Antitubercular Leprosy Interrupts the binding
of β subunit with
DNA which inhibits
mRNA production
leading to the death of
the bacteria
Ofloxacin Antibiotic Inhibits DNA gyrase,
DNA replication, and
transcription
References
[59]
[60]
[61]
[62]
[63]
[64]
86
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
Drug Original use New indication Possible mechanism
against newly
indicated disease
Dapsone Antibiotic Inhibits folate
biosynthesis in the
bacterial cells
Minocycline Antibiotic Inhibits protein
synthesis by binding
with 30S subunit of
the ribosome
Thalidomide Morning
sickness and
insomnia
Nitazoxanide Antibiotic Lymphatic Interferes with [66]
filariasis anaerobic electron
Doxycycline Antibiotic Blocks embryogenesis, [67]
Tizoxanide Antibiotic Interferes with [66]
Ivermectin Antiparasitic Increases the influx [68]
Albendazole Anthelmintic Prevents microtubule [62]
Inhibits
pro-inflammatory
cytokine TNF-alpha
transport channel
inhibits inflammation,
angiogenesis,
proteolysis, and
apoptosis
anaerobic electron
transport channel
of chloride ions by
glutamate-gated
chloride channels
as a consequence
dysfunction of the
excretory pore,
flaccid paralysis, and
death of the parasite
takes place
elongation which
interferes with
chromosome
segregation and cell
division ultimately
leading to defective
embryogenesis
References
[63]
[63]
[65]
TABLE 4.2 (Continued)
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87 Parasitic Diseases and Neglected Tropical Diseases (NTDs)
Drug Original use New indication Possible mechanism
against newly
indicated disease
Azithromycin Antibiotic
Artemether Antimalarial
Artesunate Antimalarial Impairs fecundity of
Mefloquine Antimalarial Interferes with
Synriam Antimalarial Interferes with
Edelfosine Anticancer Downregulates the
Ravuconazole Chagas disease
Sulphamethoxazole Antibiotic Inhibits folic acid
Trimethoprim Antibiotic Inhibits the activity
Linezolid Antibiotic – [77]
Trachoma
Schistosomiasis
Mycetoma
Inhibits polypeptide
synthesis
Alters glycogen
content in the parasite
adult female
hemozoin formation
hemozoin formation
function of T helper
1 and T helper 2
response, thereby
reducing granuloma
formation
– [75]
synthesis
of dihydrofolatereductase
References
[69]
[70]
[71]
[72]
[73]
[74]
[76]
[76]
Drug design, discovery, or development using computational techniques
have emerged as a cost-effective and efficient approach in the field of phar-
78
maceutical research.
Captopril (antihypertensive), dorzolamide (treatment
of glaucoma), saquinavir (anti-HIV), zanamivir (anti-influenza), oseltamivir
(anti-influenza), aliskiren (antihypertensive), boceprevir (treatment of hepatitis), nolatrexed (anticancer), TMI-005 (anti-inflammatory), LY-517717
(prevention of thrombosis), rupintrivir (antiviral), and NVP-AUY922
(anticancer) are few examples of drugs that were discovered or optimized
88
Drug Repurposing and Computational Drug Discovery: Strategies and Advances
with CADD.
21
A flowchart of the computational drug discovery process is
given in Figure 4.2. In the following section, different techniques of CADD
will be discussed in brief with special reference given to structure-based
drug design (molecular docking, MD simulations) and ligand-based drug
design (similarity searching, virtual screening, SAR, QSAR, pharmacophore
modeling). In addition, newer approaches such as the application of artificial
intelligence will also be briefly discussed.
FIGURE 4.2 Flowchart of drug discovery process involving computational approach.
89 Parasitic Diseases and Neglected Tropical Diseases (NTDs)
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4.3.1 STRUCTURE-BASED DRUG DESIGN
4.3.1.1 Molecular Docking Simulation Studies
79
Since the development of the first algorithm back in the 1980s,
has been the most widely and consistently used CADD technique.
MDSS
80–82
Even
in the ongoing coronavirus disease 2019 (COVID-19) pandemic, molecular
docking is widely used by researchers to identify potential inhibitors of
essential enzymes of severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2).
of a molecular at the active binding pocket of a known protein of interest.
83–86
MDSS can predict the binding affinity and binding pose
87
Following are a few key pieces of information that are necessary to understand the basics of MDSS:
• MDSS is used when the target proteins are known and the protein
structures are available or can be prepared.
• The X-ray 3D structure of proteins can be downloaded from the
Research Collaboratory for Structural Bioinformatics-Protein Data
Bank website (RCSB-PDB) (https://www.rcsb.org/).
• When the desired protein structures are not available on the RCSB-
PDB website, the structures of proteins are prepared manually using
the homology modeling technique.
88
• The ligands that are to be docked toward the active binding pocket
of the target protein can be prepared manually, or their structures
can also be downloaded from an online database such as PubChem
(https://pubchem.ncbi.nlm.nih.gov/), COCONUT (https://coconut.
naturalproducts.net/), etc.
• Once a ligand is docked toward the active binding site of a protein,
the algorithms of the docking software generate different binding
poses of the ligand with the first pose having the best binding affinity
(lowest binding energy) toward the target protein and so on.
• When multiple ligands are docked simultaneously, the software algo
84
rithms rank the binding affinity of the ligands by giving each ligand
a numerical score. For example, “ligand A” with a binding energy of
−10.0 kcal/mol has the best binding affinity toward a target protein
while “ligand J” with a binding energy of −1.0 kcal/mol has the worst
binding affinity toward a target protein.83 Generally, “ligand A” will
be selected for further studies.
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