*7.1.3 Fragment-based drug discovery*

It is a powerful method which is used to find out the proportion of ligands with high affinity to target proteins. The compounds which are found to have low ligand binding ability are eliminated, and the compounds with high ligand ability move forward to the precision of compounds. FBDD consists of the techniques such as NMR, SAR, X-ray crystallography, and surface plasmon resonance (SPR).

## *7.1.3.1 X-ray crystallography*

It can ascertain the binding sites and modes of ligand binding to protein [68].

### *7.1.3.2 Surface plasmon resonance (SPR)*

Surface plasmon resonance is known as a nonlabel technology that can identify, screen, and quantify intermolecular interactions in actual time. It is applied to quantify binding affinities. SPR-dependent biosensors work by detecting the ligands and immobilized target molecular interactions and supply appropriate information on kinetics of biomolecular interactions. The output information can be utilized to provide comprehensive functional data on binding actions such as specificity, kinetics, concentration, and affinity [69]. Scientific literature study revealed Biacore tools as mainly used SPR technology at commercial levels [70].

#### **7.2 Preclinical trials**

In the last 2 years, different methodologies based on high-throughput screening and their combinations with chemistry have been developed in order to manufacture versatile compounds by limiting the resources. Among these methodologies, several other in vitro and in silico supplementary approaches have also come forward for the identification and potential evaluation of these compounds as lead candidate validation. Those compounds which are selected as "hits" during this screening procedure are further analyzed and subjected to in vivo toxicity and efficacy profiling. During preclinical stage of drug development, simple formulation approaches are favored. Combinatorial chemistry and high-throughput approaches have been appraised in several publications [71].

PLOTs are preclinical lead optimization technologies that should be rapid enough to edge with high-throughput discovery screenings without causing further delay and should be predictive and cost-effective. PLOT platform usually comprised of in vitro systems, small and acquiescent to mechanization, and that is why it is easy to achieve the mandatory throughput with minimum use of compound use [72].

#### *7.2.1 Tools of preclinical drug development*

Selection of methodology and tools for selection of preclinical drug candidates is a rigorous process. Sequential approach of preclinical to clinical is practiced to sort out the long list of target selected compounds. This streamline strategy provides with deeper understanding of action of the drug prior to its progress to the next steps [73].

## *7.2.2 Pharmacokinetics and pharmacodynamics (PK/PD) during preclinical drug evaluation*

Pharmacodynamics involves the study of effect of drug in dose- and timedependent manner. Pharmacokinetics is the study of absorption, metabolization, distribution, and excretion of a drug over time. PK/PD is a program at early phase of lead drug development which acts as a bridge between drug discovery and preclinical drug development. This stage set aims for further development activities, and information obtained at this stage act as a key to subsequent steps.

**139**

*Chemical Biology Toolsets for Drug Discovery and Target Identification*

a.It provides potency-based intrinsic activity of the compound rather than dose.

b.It characterizes the compounds on the basis of dose concentration and effect

c.It allows the investigation of tolerance phenomenon of compounds on the basis

Optimization of a drug is a multifaceted process. It usually involves various types of screening methods which tend to find out the metabolism and pharmaco-

This is the final stage of preclinical trials; after this the optimized drug is further processed towards the clinical trial. Absorption, distribution, metabolism, and excretion screening is performed at this stage. The primary goal of ADME is to develop a competitive drug with adequate safety avoiding PK failure

Ideal properties of a drug in ADME testing involve the good oral bioavailability, blood clearance and volume of convenient dosing, and low potential of drug-drug interaction. All of these properties are assessed at early stage of drug discovery [76].

Drug effect is a parameter which determines the concentration of a drug which do not cause any harm at the site of action. In other words at this stage, toxicity of a drug is tested to find out the minimum safe dosage potency. In vitro DRUGeff testing of all compounds show interaction with the target treatment, until a small portion of dose gets to select according to biophase levels. Concentration of treatment dose maximization per unit of biophase acts as a key objective for lead optimization. The drugs qualifying this test enter into the clinical phase [77].

The final step of drug discovery and development is referred to as the clinical trial. At this stage, the data regarding safety and efficacy of the new drug must be proven by application to humans directly in different phases. After the successful trials, research data is sent to the FDA for approval for commercial manufacturing

The first phase of clinical trial normally takes several weeks to some months. At this stage application of optimized drug is tested on a small group of volunteers.

It is necessary because of the following reasons:

kinetic properties of selected compounds or drugs [75].

*DOI: http://dx.doi.org/10.5772/intechopen.91732*

of physiological parameters [74].

relationship.

**7.3 Lead optimization**

*7.3.1 ADME*

in clinical phase.

*7.3.3 DRUGeff*

*7.3.2 ADME properties*

**7.4 Clinical phase of drug discovery**

and marketing (**Figure 6**) [78].

*7.4.1 Clinical phase I*

It is necessary because of the following reasons:

