**7. Development of lead drug**

*Cheminformatics and Its Applications*

*5.1.3 Drug affinity responsive target stability (DARTS)*

target proteins [61].

interactions [61].

**6. Hit generation**

and clinical phase trials.

stabilization of target proteins. The compound-treated cell lysates and intact cells were heated to different temperatures, and in the soluble fractions, the target protein was separated from destabilized protein and detected by Western blotting. SPROX is a method of target validation based on identification of ligand-induced stabilization of target proteins. It evaluates the levels of methionine oxidation of

DARTS has been used for the identification of the targeted proteins. It is based on ligand binding interaction with proteins forming a complex which changes the structural stability of target protein. There alteration is measured by SDS page/ liquid chromatography. DARTS is also involved in the analysis of the low affinity

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

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

**136**

**Figure 5.**

*compounds.*

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 optimization and preclinical and clinical trials [64].

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 selection and the method of identification [65].
