**4.2 Lead prioritization and optimization**

 A number of leads will be generated as a result of any screening programme. One of the most important considerations in the drug development process is deciding which lead to prioritize. Compounds can be prioritized via metabolic profiling based on their capacity to generate the desired biochemical changes. Prioritization is now based on response strength and theoretical considerations of metabolism and toxicity. An inaccurate guess at this time could lead to the failure of the entire programme. A metabolomic analysis can help to distinguish the leads based on their primary and secondary reactions.

 In order to progress from a lead to a therapeutic candidate, the lead is employed as a basis structure for the synthesis of hundreds of derivatives in a process known as "lead optimisation." In this step, chemists make several changes to the initial lead and test the impact of the alterations on activity. Each lead is assigned a metabolic profile, and the lead is optimized depending on the profile. This procedure is continued until the final lead candidate with the fewest secondary effects is chosen [ 41 – 44 ].

*Metabolomics: Special Emphasis on Basic Drug Discovery and Development DOI: http://dx.doi.org/10.5772/intechopen.112969*

#### **4.3 Target identification and validation**

Identifying bioactive molecule targets is a major difficulty in chemical biological research. Metabolons, a proprietary technology platform, allows researchers to precisely gauge the multitude of metabolic alterations inherent in a specific disease and then map these changes to known pathways, helping them to better understand the disease.to establish a biochemical hypothesis for an ailment quickly. Based on this concept, illness-causing enzymes and proteins can be identified, and druggable disease targets can be located [7]. There are two basic methods for identifying chemical inhibitor targets: direct and indirect. The target proteins bound to the inhibitor are isolated and immediately identified by mass spectrometry in the direct technique. The indirect technique to identifying chemical inhibitor targets is searching for candidates by profiling biological data. If the drug was discovered to disrupt some cellular event for which the regulatory signaling pathway is known, targets can be identified by studying the compound's influence on each stage of the pathway. In some circumstances, omics research (for example, proteomics, transcriptomics, and metabolomics) can aid in the thorough analysis of a compound's effect on a potentially huge number of biological stages. Metabolomic profiling approaches gives the information about the biochemical fingerprint for a specific target. The target can be biochemically validated by identifying any unanticipated adverse effects and by comparing the target to the disease itself. It is also feasible to discover unanticipated secondary effects inherent in a target, so as to discard a target that may pose prohibitive risk [45, 46].

#### **4.4 Biomarker identification**

Being able to quantitatively detect, measure, or monitor the disease for which the medicine is being created is crucial to drug development. A medicine to treat a disease cannot be produced until the disease is measured. Many of today's disease assays and diagnostic tests utilize small molecules (i.e., Metabolite) biomarkers as indicators of disease or condition (absence/presence/severity). Metabolomics is primarily concerned with the detection and quantification of small molecule biomarkers (i.e., biomarkers for disease and therapeutic efficacy). Metabolomics has already been used to identify small molecule biomarkers or multi-metabolite signatures for a wide range of diseases such as hypertension, heart failure, Parkinson's disease, prostate cancer, breast cancer, ovarian cancer, schizophrenia, Alzheimer's disease, and coronary heart disease, etc. [47–56]. The most successful application of metabolomics is to discover inborn errors of metabolism (IEMs), with NMR-based metabolomics capable of identifying and monitoring more than 85 different IEMs and MS-based metabolomics capable of detecting and monitoring 130 different IEMs. (For example, phenylketonuria can be diagnosed by low tyrosine levels, Tay Sachs disease by high GM2 ganglioside levels, and cystinuria by high lysine and cystine levels.) [36, 57].

#### **4.5 Mode of action**

The justification of MoA using metabolomics usually demands prior information on the impacted metabolic pathways. In other words, drug-induced metabolic changes are statistically analyzed using route maps, and the most significantly affected nodes (proteins) are then selected for additional investigation/validation. This type of analysis can be performed by combining untargeted metabolomics with in silico or chemoinformatic techniques [58]. It can be utilized to predict not just the mode of action of the drug, but also the harmful mechanism of action [7**]**.

#### **4.6 Measuring drug metabolism**

ADME testing is one of the most important aspects of drug development process. The process is very time consuming, expensive and error-prone [59]. The emergence high throughput metabolomic methods has opened up a new avenue for experimentally monitoring ADME and identifying metabolites and metabolic pathways associated with drug metabolism [60]. Methods for identifying drugs or drug metabolites rely more directly on experimental data analysis and spectral comparisons of dosed and un-dosed bio samples. These include mass defect filtering techniques [61] and multivariate data analysis of LC-MS chromatograms for MS and STOCSY for NMR spectroscopy, which can be used in conjunction with high resolution MS instruments such as FTICR (Fourier Transform Ion Cyclotron Resonance) or OrbitrapTM [60] spectrometers to generate exact molecular formulas. Compound identification is clearly only a subset of what is usually necessary for full ADME experiments. It is crucial to measure the amount, distribution, and location of a substance once it has been identified. It is also crucial to compare these results to those of other metabolites over time and space, and to conduct these measurements using additional biological or technical replicas. Fortunately, the high-throughput characteristic of most metabolomics technologies enables these multicomponent, multi-sample analyses to be carried out with great repeatability and at a reasonable cost [61].

#### **4.7 Preclinical study**

Metabolomics approaches can be applied rapidly and noninvasively in a number of toxicological assays such as Identification of target organ or region of toxicity, identification of biochemical mechanism of toxicity, identification and quantification of biomarkers profile which measure toxic effects, measurement of time course of toxic effects [62]. This can be employed as a safety screening mechanism by many pharmaceutical companies as an alternative to expensive and time-consuming toxicological and histopathological screening. Furthermore, it can be utilized to find toxicity biomarkers as a result of the identification of various biomarkers utilizing this platform [63].

#### **4.8 Clinical study**

Clinical trial monitoring and screening is very important in the drug discovery and development process. Clinical trial monitoring not only involves the effect of drug but also involves the influence of diet, drug use/abuse and behavioral factors on the outcome. Metabolomics can be can be useful in-patient monitoring by detecting the presence of over-the-counter drugs, herbal supplements, drugs of abuse and food by products in clinical trials settings to assure patients compliance [64–67]. This method be useful in the patient screening and drug patient matching. This approach can be utilized to examine drug metabolism characteristics in individual patients. There is significant diversity in patient responses to specific classes of medicines (such as antidepressants), which is largely owing to differences in drug metabolism profiles [68]. Certainly, detecting susceptible/refractory patients prior to recruitment (in clinical trials) or prescription (in clinical practice) would improve outcomes. The use of metabolomic-based phenotyping in clinical trials or drug dosage in clinical practise

#### *Metabolomics: Special Emphasis on Basic Drug Discovery and Development DOI: http://dx.doi.org/10.5772/intechopen.112969*

has the potential to be a quick and low-cost screening method for patient selection or drug dosing. These metabolomic assays would almost certainly be far less expensive in terms of both time and money than traditional approaches. Metabolomics is extremely effective in monitoring drug doses of relatively toxic pharmaceuticals (anticancer drugs such as methotrexate, 6-mercaptopurine, 5-flurouracil, etc., blood thinning agents such as warfarin, immunosuppressants such as mycophenolic acid and ciclosporin). Furthermore, it plays a critical role in detecting and monitoring ADRs, which are a huge burden for the pharmaceutical business and healthcare system (due to patient death and hospitalization). Endogenous metabolite levels in the blood and urine can be used to detect many undesirable medication effects [61].

## **5. Challenges for metabolomics**

Data analysis is one of the most difficult aspects of metabolomics research. Metabolomics provides enormous volumes of data, often with complicated structures and patterns that necessitate the use of advanced computer techniques to analyze.

A second difficulty is sample deterioration and standardization. Metabolomics is a young discipline with few widely agreed standards for sample collection, processing, and analysis. Importantly, after a sample is extracted, its metabolic signature may differ from what it was in the biological system. This emphasizes the importance of sample preparation and makes comparing results between research and replicating trials challenging.

Another issue is the existing metabolomics techniques' lack of sensitivity and specificity. Despite substantial technological breakthroughs, contemporary metabolomics techniques are still incapable of detecting all metabolites in a given sample. This can result in false negatives or incorrect results [69].

### **6. Conclusion**

Metabolomic principles have the potential to revolutionize the drug discovery and development process. Metabolomics focuses on the small molecules that are essential for life to exist and act as the molecular foundation for cells by supplying fuel for cellular processes. Small molecules also help to preserve cellular integrity, fights environmental stress, and acts as a cellular messenger for a variety of cellular activities. Drug discovery is a time-consuming, high-risk, and tremendously expensive procedure. Metabolic profiling is a sensitive indicator of phenotypic alterations as well as pharmacological on and off target of drug candidates. High-resolution metabolic profiling is possible using minimal sample preparation, and as part of various drug testing processes. Metabolomics can also offer drug selection markers that can be employed *in vivo* which are phenotypic specific.

Metabolomics allows scientists to investigate the known roles of small molecule metabolites in greater detail and with better precision than ever before. The increasing breadth of available coverage, increased sensitivity, greatly improved analytical software, and trends towards more accurate quantification enable certain types of novel metabolomics experiments that were only a dream a few years ago. Continuing development in the field metabolomics along the growing investment by the pharmaceutical industry players and FDA will foster a rapid and more cost-effective drug discovery and development process.
