Metabolomics in Drug Discovery: A Review

67 International Journal of Pharmacy and Pharmaceutical Science Research 2011; 1(2): 67-74

ISSN: 2249-0337

Review Article

Metabolomics in Drug Discovery: A Review

Martis Elvis A.*, Ahire Deepak C., Singh Ruchi O. Department of Pharmaceutical Chemistry, Vivekanand Education Society’s College of Pharmacy

*Email: [email protected].

Received 17 July 2011; accepted 30 July 2011

Abstract

Metabolomics is up-coming omic science. Metabolomic society consistent with other post genomic sciences such as genomics,

transcriptomics and proteomics. Metabolomics is emerging as a significant player in drug development process, it is a

technology that aims to identify and quantifies the metabolome-the dynamic set of all small molecules present in an organism

or a biological sample. Metabolic analysis provides a biochemical snapshot of the small molecules produced during cellular

metabolism. Since the metabolome directly reflects physiological states, it can biochemically monitor disease states and assess drug actions, improving the preclinical to clinical translation and focusing on predictability, efficiency and improve

productivity. Knowing early on how drugs impacts biochemistry would be a significant advantage, leading to fewer failures at

a later stage. This paper describes about metabolomics as an important tool in drug discovery and also gives an overview

metabolomic process.

© 2011 Universal Research Publications. All rights reserved Key words: Omic Science, Metabolomics, Drug Discovery.

[1] Introduction:

Any Pharmaceutical Company to survive in this

competitive market, where newer therapeutic agents for various illnesses are being launched at very high frequency,

must invest a good deal of resources in drug discovery

process. They must break through and investigate numerous

possibilities to invent newer, effective and safer drugs. The

scenario of drug discovery process has received a many fold

facelift, during the beginning of the 21st century. Figures

(Fig. 1A, Fig 1B and Fig 1C) illustrates the comparison of

the process in 50’s, 80’s and present day scenario.[1] Omic

science encompasses studies in, transcriptomics [2],

proteomics [3] , metabolomics [4] , genomics [5], fluxomics

[6].

Here are some terminologies related to metabolomics: [1.1] Metabolite- It is a substance produced or used during

metabolism.

[1.2] Metabolome- The quantitative complement of all the

low molecular weight molecules present in cells in a particular physiological state. It refers to the catalogue of

those molecules in a specific organism, e.g. Human

metabolome.

[1.3] Metabolomics- Study of treasury of non-proteinaceous

endogenously synthesized small molecules present in

organism. Metabolomics is a comprehensive analysis of the

whole metabolome under a given set of conditions.

Metabolomics is the only technology that provides

information about the quantitation of, the interactions

between the genome, proteome and biological ‘wild card’

that is the external environment.

Metabolomics is up-coming omic science. Metabolomic society is consistent with other post genomic sciences; ideally

Available online at http://www.urpjournals.com

International Journal of Pharmacy and Pharmaceutical Science Research

Universal Research Publications. All rights reserved

http://www.urpjournals.com/


Figure-1 (a): Drug discovery process in 1950’s and 1960’s

Figure-1 (b): Drug discovery process in 1980’s

Figure-1 (c): Present day drug discovery process.[50]

metabolomic data sets will be combined with their other omic

sciences, providing complete views into the molecular

pathways of system biology. However, rather than focusing

on characterizing large macromolecules (DNA, RNA and

proteins) as happens in genomics or proteomics,

metabolomics is focused on characterizing the small

molecule, catabolic and metabolic products arising from the

interactions of these large molecule (Fig 2). [7, 8]


[2] Metabolome Analysis:

Absorption, distribution, metabolism and excretion (ADME)

studies are widely used in drug discovery to optimize the

balance of properties necessary to convert leads into safe

drugs. Recently, metabolite characterization has become one

of the main drivers in the drug discovery process, helping to optimize ADME properties and increase the success rate for

drugs. It has been a valuable and useful part of the drug

development process for several decades [8]. During the past

decade there has been an increased effort to address

metabolism issues using high throughput technology for

screening compounds, which in turn has led to strong demand for more rapid methods for metabolite identification [9].

Figure-2: The omic sciences are characterized by complex data sets

of related phenomena, each of which is taken, as a whole constitutes

a picture of an organism.

Figure-3: Strategies for metabolomic investigations.


Figure-4: The circle shows particular area of metabolism that is affected, once identified, the

targets, the protein or enzyme involved in creating the metabolic change can be detected.

Figure-5: A diagram of the pharmaceutical value chain, which indicates the biomarkers and this information, can be

applied to various stages in the drug development process.


Metabolite characterization earlier in process can identify

metabolic pathways for drug candidate. Metabolite structural

information eliminates potential harmful candidates earlier in

the process & improves safety. There are two different

approaches for collecting, processing and interpreting

metabolomic data [10]. [2.1] Chemometric approach: The approach is based on

computer-aided Pattern recognition and sophisticated

statistical techniques such as principal component analysis

(PCA) [11].

[2.2] Chemonomic approach: Chemonomic approach relies

on spectral fitting and prior chemical or spectral knowledge

about the tissue or biofluids such as Urine, Plasma, and

Serum [11].

Modern approaches that generate and use metabolite

structural information can accelerate the drug discovery and

development process by eliminating potentially harmful

candidates earlier in the process and improving the safety of new drugs [12].

[3] Methods of Characterization (Fig. 3) [13-19]:

Separation methods: - Gas Chromatography, High

Performance Liquid Chromatography

Detection methods: - Mass Spectrometry, Nuclear Magnetic

Resonance.

[3.1] In- Silico Screening:

It predicts & finds possible metabolites and its chemical

structures and it is having ability to screen large number of

structures even before synthesis [12, 20, 21]. E.g. TOPKAT,

CASE/MULTI-CASE, DEREK, EXPERTHAZARD, METAPRINT.

Today different techniques are combining for better

resolution, such as LC-MS, Instrumental techniques LC-MS-

NMR have become commercially available to confirm and

characterize metabolites. Hydrogen-deuterium (H-D)

exchange and dramatization methods in conjunction with MS

Facilitate structural elucidation and interpretation of tandem

mass spectrometry (MS/MS) fragmentation processes [14].

[4] Working of Metabolomics:

Multitudes of proteins are organized into signal transduction

pathways that function to perceive inputs and trigger outputs. The inputs can be highly varied, from hormone or

neurotransmitter signaling to changes in the physical

environment, the ultimate outcome of these signaling

pathways is that metabolic enzymes may be up or down

regulated, and this influences the synthesis or degradation of

the small molecules. In metabolomics, we measure the

repertoire of small molecules in a sample (e.g. cells, tissues,

organs, organisms) to understand more clearly what has

changed in a system. Metabolomics as a measure of

biochemistry is a more direct measure for a disease state (Fig.

4) [7].

[5] Role in Drug Discovery: Metabolomics has broad applications across the drug

discovery and development processes. Metabolon’s

proprietary technology platform in metabolomics will enable

faster and more cost-effective processes [22] in the following

areas:

[5.1] Target Identification:

Metabolon has the ability to determine accurately the treasury

of biochemical changes inherent in a given disease, and then map these changes to known pathways, allowing researchers

to build a biochemical hypothesis for a disease quickly.

Based on this hypothesis, the enzymes and proteins critical to

the disease can be elucidated and druggable disease targets

identified [23, 24].

[5.2] Target validation [25]:

With Metabolon’s approach of metabolic profiling, we

determine the biochemical fingerprint for a specific target.

The target can be validated biochemically in two ways:

a. By determining any unexpected side effects inherent in it.

b. By comparing the target with the actual disease.

With metabolomics, it is possible to see unanticipated secondary effects inherent in a target and thus abandon a

target that may carry unacceptable risk [23].

[5.3] Lead prioritization:

From any screening programme, a number of leads will be

found. In one of the critical decisions of the drug discovery

process, one must choose which lead has highest priority.

Using metabolic profiling compounds can be prioritized

based on their ability to cause the desired biochemical

changes. Currently, prioritization is based on strength of

response and theoretical considerations of metabolism and

toxicity. An incorrect guess at this point may doom an entire programme to failure. A metabolomic analysis makes it

possible to classify the leads separately based on their

primary and secondary responses [26, 27].

[5.4] Lead optimization:

To move from a lead to a drug candidate, the lead is used as a

base structure for the synthesis of hundreds of derivatives in a

process known as ‘lead optimization’. In this step, chemists

make many changes to the original lead and determine the

effects that the changes have on activity. A metabolic profile

is determined for each lead, based on profile, lead is

optimized. This process repeated until final lead candidate with the lowest secondary effects is selected [28, 29].

[5.5] Mode of action:

Metabolon has the ability to cluster drug candidates

according to their common mechanism of action. Based on a

metabolomic analysis, a hierarchical clustering or principal

component analysis of compound profiles for drug candidates

can be performed. The ability to cluster drug candidates

according to their common mechanism of action has proved

very useful in predicting the mechanism of unknown drug

candidates. The predictive power of this type of analysis

provides a significant benefit for prioritizing drug candidates.

It can not only be put to use to predict the mode of action of the drug, but also be used to predict the toxic mechanism of

action [30-34].


[5.6] Preclinical studies:

Metabolon’s technology will be highly valuable in preclinical

studies to differentiate drug leads based on their non-target

tissue effects. Sometimes, these effects occur in the targeted

tissues, but often they occur in non-targeted tissues and the

undesired biochemical changes can lead to toxicity. In this case, Metabolon can evaluate compounds in advance of

clinical trials to assess their relative probability for causing

side effects [35-37].

[5.7] Clinical studies:

Using Metabolon’s unique approach to drug development the

time in clinical trials can be shortened thereby making

quicker availability of the drugs in the market. Metabolon can

identify subsets of patient populations within a given

disorder. For this subset, the compound will have a higher

safety and efficacy profile [38, 39].

Once this subset is identified, Metabolon can assist in the

design of clinical trials to target that subset population. Since the design of the study is focused on patients that are more

likely to respond to the drug and have fewer side effects, the

enrolment necessary should be less, allowing for faster and

less expensive clinical trials [8].

Phase I: These trials are small and meant to establish safety.

Phase II & III: These trials establish efficacy and safety

biomarkers.

[5.8] Post-approval studies:

Metabolon can provide comparative studies for marketing

purposes to demonstrate safety and efficacy. Drug effect

comparison studies are not only useful for marketing purposes, but can presented to the US Food and Drug

Administration (FDA) to differentiate competitive drugs in

order to avoid class labeling. In addition, technology

platforms are useful for sorting the complex chemistry of

clinical samples [7, 8].

[5.9] Diagnostic:

Metabolon can identify biomarkers for various disorders.

With these biomarkers, metabolon will associate with

diagnostic companies to develop diagnostics. After reviewing

a certain population of healthy and diseased analysis,

Metabolon can identify biomarkers that become diagnostic of a given disease [40-44].

[6] Role in Solving Translational Chasm:

Today few drug discovery projects generate a marketed drug

product, because preclinical studies fail to predict the clinical

experience with a drug candidate. Improving the preclinical

to clinical translation is important in optimizing the

pharmaceutical value chain. the gap between preclinical

studies and clinical trials is referred to as the ‘Translational

Chasm.” (Fig. 5) Metabolomic focusing on predictability,

efficiency and Improve productivity by crossing the

translational chasm via molecular system approach.

Molecular system analysis of biofluid is performed; it permits molecular phenotyping primarily by proteomics and

metabolomics [45-47].

[7] Role in Reverse Translation:

Crossing translation chasm in reverse direction enables

discovery of second-generation drugs with improved efficacy

& safety characteristics relative to first generation drug. The

drug passed back to the preclinical phase from clinical trials

or post marketing studies. Second-generation discovery based on Mode of Action of first generation. Plasma or serum

metabolite profiling of blood samples, derived from patients

treated with a first generation drug vs. placebo for a disease,

yields system response profiles. Including biomarker sets that

can be statistically associated with efficacy or safety outcome

measures [45, 46-49].

[8] Conclusion:

Metabolomics is emerging science; it enables faster & more

cost effective process in drug discovery & development

process. It offers toolkit, which can be potentially applied to

identification of biomarkers, biochemical pathway studies,

and diagnostic monitoring and tracking of mechanisms associated with disease. It offers promise that yet to be

fulfilled by post-genomic sciences. It increases efficacy and

safety of drugs. Genomics & proteomics tell what might

happen but metabolomics tells what actually did happen.

Metabolic profile gives knowledge & information rather than

just data.

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Source of support: Nil; Conflict of interest: None declared

Metabolomics in Drug Discovery: A Review

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