Overview of the Drug Discovery Process

The steps of drug discovery can be simply summarized as disease→target→hit→lead→candidate→drug.

Disease Selection

Target Selection

After the disease that needs to be overcome is identified, biologists need to study the mechanism of the disease and finally determine the target. Targets refer to those biochemical structures that can be recognized by drugs in the biological pathways of diseases, usually proteins (including ion channels), nucleic acids, etc.

Target selection is a critical process. We need to consider whether the selected target can interfere with the development of the disease, whether it is safe, and whether it can be druggable (that is, whether a molecule can be designed to react with the target).

There are about 22,000 genes in the human body, of which 5,000-10,000 genes are related to diseases, and about 3,000 are suitable as targets for drug therapy. The intersection of the latter two is our research object, and there are currently about 120-400 targets being studied.

Targets suitable for drug therapy are mainly (in order of number): kinase (Kinase), G protein-coupled receptor (GPCR), ion channel (Ion Channel), protein phosphatase (Portein Phosphatase), serine protease (Serine protease) Protease), zinc peptidase (Zn peptidase), cytochrome P450 (CYP), nuclear hormone receptor (Nuclear Hormone Receptors), carboxylase dehydrogenase (Dehyrogenases)/reductases (reductases). Among them, kinases, GPCRs, ion channels, cysteine proteases, serine proteases, zinc peptidases, CYPs, and nuclear hormone receptors have been widely used as targets for target selection.

So how to choose a target? Traditional methods include analyzing the chemical structure or chemical function of known targets and screening known collections of compounds. More recent approaches include proteomics and RNA interference. Chemistry played a big role in this process.

Target analysis needs to consider the following questions: How similar are the target and related proteins? - involves the question of specificity; to what extent is the target involved in normal physiological function? - Involving safety and tolerance; are there known lead drugs for this or related targets? - At the same time related to drugability (drugability), safety and specificity.

Hit Identification

A hit compound is usually a compound that is known to have some activity (usually 5-0.5 μM) against the target protein or other structurally related compounds. The discovery of hit compounds requires high-throughput screening, virtual screening, de novo drug design and other methods to obtain compounds with brand-new skeletons and preliminary biological activities for further transformation and modification.

Hit-to-Lead

Finding lead compounds from hits is a critical step in drug discovery. In this step, small molecule hits after high-throughput screening are evaluated and preliminarily optimized to obtain a series of lead compounds. A lead compound is a compound with pharmacological or biological activity, the chemical structure of which can be further optimized to enhance potency, selectivity, and improve pharmacokinetic properties.

Lead Optimisation

Once the initial lead compound has been identified, it is necessary to start designing candidate drugs on this basis, a process called lead compound optimization. A drug candidate is a compound selected from the lead compound series that satisfies the preliminary entry into clinical trials. During lead optimization, potential drugs are continuously synthesized and characterized to understand the relationship between chemical structure and activity through experiments on interactions with targets and metabolism.

Candidate Selection

Chemistry plays a pivotal role in the process from target selection to drug candidate identification. When a drug candidate is discovered, we can send the candidate drug for clinical trials. After pre-clinical animal tests and Phase III human experiments, a long time for approval and registration from the regulatory authorities is required before a new drug can finally be mass-produced and marketed.