**13.3. Preclinical trials**

This is the screening of a large number of natural products, chemical entities, large libraries of peptides, nucleic acids and other organic molecules for biological activity. This approach may

This is the profiling of natural products of related plant species screening using either liquid or gas chromatography mass spectrometry to determine active metabolites that may be present

This is the most advanced technique for drug discovery. It entails virtual screening or docking of compounds on the 3-D- structure of a known receptor based on homologies of the test drug molecules with a known test parent drug. *In silico* screening can form a basis for the modifi‐ cation of a known drug molecule to determine possible therapeutic applications and may lead

Selection of molecules for further study is usually conducted in animal models of human disease and the pharmacological tests include both the *in vitro* and *in vivo* studies after the initial screening for biological activity. For instance, antibacterial activity of drugs is assessed by their ability to inhibit growth of a variety of micro-organisms, while hypoglycemic drugs

The *in vitro* methods include incubation of a parent compound with various subcellular fractions such as microsomes, individual recombinant drug metabolizing enzymes from cells or tissue slices. The *in vivo* studies involve working on typical animal models such as dogs or rats. Some of the *invitro* and *invivo* studies that may be performed are shown

**Target Specific or tissue in vitro studies Biochemical measurement**

(ii) Receptor activity Sympathetic nerves Inhibition of nerve activity

Receptor affinity

relaxation

Inhibition of enzyme activity

Effects on vascular contraction and

lead to identification and development of new drug molecules.

to the development of putative drugs against new targets.

in novel crude herbal medical preparations.

**13.2. Screening of putative drug molecules**

are tested for their ability to lower blood pressure.

a. (i) Receptor binding Cell membrane fraction / cloned

(iii) Enzyme activity Purified enzymes from adrenal

c. Isolated tissue Blood vessels, heart lung or ileum

receptors

glands

b. Cellular function Cultured cells Cell viability

from rat

**Table 1.** Screening of drugs for specific inhibitory effects on enzymes and isolated tissues.

**Metabolomics**

498 Drug Discovery

*In silico* **screening**

in tables 1 and 2 below;

e.g. tyrosine hydroxylase

The data from animal studies form a basis for the calculation of the initial or starting doses to be used in the subsequent clinical studies. The human equivalent dose calculations for the maximum recommended dose are normally based on either the body surface area or body weight. The candidate drugs that survive initial screening and profiling must be carefully evaluated for potential risks before and during clinical testing. The main types of evaluation needed from safety and toxicity studies include:-

#### **Acute toxicity**

This involves looking at the effects of large single doses of therapeutic agent. Acute toxicity studies are usually performed in animal models such as mice and rats. These studies enable investigators to correlate any observed effects with the systemic level of the drug.

#### **Sub-acute toxicity**

This is similar to acute toxicity but measures the effects of multiple doses based on expected duration of clinical usage. It entails haematological, histology and electron microscope studies to identify organs which might be affected by toxicity. It usually lasts between one to three months. This enables the selection of putative compounds for subsequent studies.

#### **Chronic toxicity testing**

These studies are required when the drug is intended to be used in humans for prolonged periods. The goals of this investigation are mostly similar to those of sub-acute toxicity.
