**6. Hit generation**

Hit identification is considered as the significant bottleneck for lead generation success and for new medicines. An example for random hit identification is physical and biochemical testing [62]. The journey of a compound from the hit status to lead status follows a series of steps which have been briefly illustrated in **Figure 5**. The figure describes a note of possible techniques which could be utilized for the selection of lead compounds and proceeding them through lead optimization preclinical and clinical phase trials.

#### **Figure 5.**

*A diagram elaborating the significant steps of lead optimization proceeding to clinical phase of natural compounds.*

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*Chemical Biology Toolsets for Drug Discovery and Target Identification*

Pharmaceutical companies are facing constant economic pressure to bring efficacy in drug discovery and development process. Lists of compounds obtained after hit optimization are further subjected to refining process in order to find out the lead compounds that can be analyzed for production at commercial scale. During this "hitto-lead" refining process, many compounds are dropped out due to inadequate absorption, distribution, metabolism, excretion, and toxicity/ADMET characteristics [63]. Refining of hit compounds to lead compound is done through the process of secondary screening. Almost 50% of all drug candidates thin out during optimiza-

There are many approaches available for the discovery and development of drug which might follow different pathways to optimize the compounds into bioavailable drugs. All these pathways must have a common origin; they all begin with a lead compound. It is necessary to go through the phylogeny study of all the compounds because there are some properties like solubility, target affinity, toxicity, ease of synthesis, and bioavailability, all of which are highly dependent on the initial lead

A rational approach is used to select lead drug candidate after optimization of hit compounds. There are many methods which can be used for screening of compounds. Selection of techniques depends upon the source of hit compounds and types of their solvents as well. The following techniques are useful in selection.

Quantitative structure-activity relationship model is used to compare chemical structures by using database of prior selected active compounds. Different software like ChemBioOffice Ultra 1.11 is used to generate two-dimensional and threedimensional structures. The results of QSAR can be validated by using statistical

It is called as Bayesian approach. It provides with proficient understanding of shape features, hydrophobic nature, and electrostatic properties of the compounds. All of these features lie under the structure–activity relationship of selected compounds from hits. Structure data analysis of SAR is obtained in 3D form. Other results are obtained in diverse type of interrelated biochemical data, i.e., average of activities and region explored analysis. The results obtained from average activity show a common part in active compounds, and region explored data exhibit the

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).

approaches like correlation coefficient and regression coefficient [66].

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

tion and preclinical and clinical trials [64].

selection and the method of identification [65].

**7.1 Techniques of lead selection**

*7.1.1 QSAR model development*

*7.1.2 Visualization of SAR activity*

areas of fully explored compounds [67].

*7.1.3 Fragment-based drug discovery*

**7. Development of lead drug**
