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Summary
on Drug Repositioning

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Zirsanglal Tripura

Trainee, SCIS , JNU

Dated: 29/01/2018

Drug Repositioning or drug repurposing is one of the most effective
method of drug discovery, its basic principle is finding a new target
for existing drug, this practice is commonly practiced by
phermacutical companies during the drug discovery process in order to
adjust or expand the application line of the active
molecule1.History of Drug repositioning came from long back before
the systamatic effort came to existance (e.g 2006) coz during the
past discovery of new uses of old drugs is mostly through
serendipity2. Here in Table 1 shows the new indiacations of drugs
and the year of approval.

Table 1.List
of repositioned compounds updated and supplemented with information
on compound approval

Drug

Original indication

New indication

Year

Amphetamine

Stimulant

Hyperkinesis
in Children(attention deficit hyperactivity disorder, ADHD)

1943

Allopurinol

Tumor
lysis syndrome

Gout

1967

Zidovudine

Cancer

HIV/AIDS

1985

Minoxidil

Hypertension

Alopecia

1988

Bupropion

Depression

Smoking
cessation

1997

Sibutramine

Deprassion

Obesity

1997

Finasteride

Benign
prostatic hyperplasia

Alopecia

1997

Methotrexate

Cancer

Rheumatoid arthritis

1999

Fluoxetine

Depression

Premenstrual dysphoric disorder

2000

Atomoxetine

Parkinson’s disease

ADHD

2002

Thalidormide

Morning Sickness

Multiple myeloma

2003

Cymbalta

Depression

Diabetic peripheral neuropathy

2004

Topiramate

Epilepsay

Migraine

2004

Paclitaxel

Cancer

Restenosis

2004

Drug repositioning became a promising, fast, and cost effective
method that can overcome traditional de novo drug discovery and
development challenges of targeting neuropsychiatric3 and other
desiseases like the neglected tropical diseases. Drug repurposing are
growing significantly growing as for non–profit organizations, in
association with academia and pharmaceutical companies, are running
screening campaigns for the identification of new repositioning
candidates4. One of the main reasons for the sucess of drug
repositioning is because a repositioned drug does not require long
term duration (i.e 6-9 years) for the development of new drugs, but
instead goes directly to preclinical testing and clinical trials,
thus reducing risk and costs5. One of the well-known examples is
sildenafil citrate (brand name: Viagra), which was repositioned from
a common hypertension drug to a therapy for erectile dysfunction 6.

General Strategies applied for Drug repositioning

Genome: In this type of drug repurposing stratagy cellular
function at genome level is understood and target is choosed via
genomic and transcriptomic data for a diverse set of disease. Some of
the method use are CMAP7 , Guilt by Asociation, Gene Silencing,
Genome Wide Association studies(GWAS) CMAP aims to construct a
detailed map for functional associations among diseases, genetic
perturbations and drug actions. By integrating with other functional
genomics databases e.g. NCBI Gene Expression Omnibus (GEO), are
extensively explored in drug repositioning studies.

Guilt by association finds for drugs that has similar
transcriptional responses which estimates that they could have same
mode of action (MoA)8

Gene Silencing , some non coding sequences act as gene silencing eg.
MicroRNA or miRNA act as RNA silencing and post transcriptional
regulation of gene expresion, thus becoming a theraputic target for
drug repositioning9.
A
genome-wide association study (GWA study, or GWAS),
also known as whole genome association study (WGA study,
or WGAS), is an study of a genome-wide set of genetic varients
in different individuals to find out any variant is associated with a
trait it typically focus on associations between single nucleotide
polymorphisam (SNPs) and traits like major human & other
organisam diseases10.

Phenome:
Its a study of pheotypic
relationship of the disease related associations which has became a
emarging area of drug repositioning work. Some organisation like
PheWAS(Phenome wide Association Studies) recently came up and became
popular with their approach to identify genetic associations with
human diseases.11

Drug Chemical Structure:
The chemical structure of
the drug can also be an important point towards reposition of drug ,
the avaibility of huge ammount of of biochemical data in opensource
databases gives useful information of drug repositioning. The
key reason behind this concept is molecules with similar chemical
structure offen affect proteins and biological systems in the same
way.

For example, Swamidass et al. 12 proposed to use chemical structure
to deduce which targets modulate disease-relevant phenotype. Knowing
which targets modulate disease-relevant phenotypes is a signal that
can indicate what other drugs might work to treat the disease.

Drug Combination:

Referances:-
1.
Croset,
S. (2014). Drug
repositioning and indication discovery using description logics
(Doctoral dissertation, University of Cambridge).
2.
Bolgar B,
Arany A, Temesi G. et al., Drug repositioning for treatment of
movement disorders: from serendipity to rational discovery
strategies. Curr Top Med Chem 2013;13(18): 2337–63.
3. Lee,
Hyeong-Min, and Yuna Kim. “Drug repurposing is a new opportunity
for developing drugs against neuropsychiatric disorders.”
Schizophrenia
research and treatment
2016 (2016).
4.
Ferreira,
Leonardo G., and Adriano D. Andricopulo. “Drug repositioning
approaches to parasitic diseases: a medicinal chemistry perspective.”
Drug
discovery today
21.10 (2016): 1699-1710.
5.Ashburn,
T.T. and Thor, K.B. (2004) Drug repositioning: identifying and
developing

new
uses for existing drugs. Nat. Rev. Drug Discov. 3, 673–683
6.Novac,
N. (2013) Challenges and opportunities of drug repositioning. Trends
Pharmacol. Sci. 34, 267–272
7.Lamb,
Justin, et al. “The Connectivity Map: using gene-expression
signatures to connect small molecules, genes, and disease.”
science
313.5795 (2006): 1929-1935.
8.Iorio
F, Rittman T, Ge H, et al. Transcriptional data: a new gateway to
drug repositioning? Drug Discov
Today 2013; 18(7–8):350–7.
9.Xing,
Zhiwei, et al. “MicroRNAs and anticancer drugs.” Acta
Biochim Biophys Sin
46.3 (2014): 233-239.
10.Sanseau
P, Agarwal P, Barnes MR, et al. Use of genome-wide association
studies for drug repositioning. Nat Biotechnol2012;30(4):317–20.
11.
Hebbring
SJ. The challenges, advantages and future of phenome-wide association
studies. Immunology 2014;141(2):157–65.
12.Swamidass
SJ. Mining small-molecule screens to repurpose drugs. Brief Bioinform
2011; 12(4) :327–35.