What is a lead?
Before getting into drug design or drug discovery, we must know what a lead is on which drugs are designed.
Lead is basically a compound or a tiny organic molecule which shows desired biological action on any validated molecular target. It can be any organic/inorganic compound.
Where leads can be found?
Leads can be found easily in libraries like peptide libraries, carbohydrate libraries or natural product libraries. We can also create Virtual Libraries by using combinatorial chemistry.
Lead Identification and Technologies Involved
The process of lead identification is carried out with following technologies:
- Actual screening
Actual screening is actually a part of chemi-informatics and is used to identify lead. In this, compound screening or docking based on protein structure is involved and molecule based chemical similarity search is carried out. There are some important considerations before carrying a virtual or actual screening. E.g. which type of compound you are going to put against receptor, structure of the receptor, general receptor ligand interactions and basic knowledge of drugs along with their characteristics.
It combines biology and chemistry with statistics, computer science and mathematics. Analysis done in chemoinformatics has focus on very big type of databases like as macromolecular structure, compound libraries and 3-dimensional chemical databases.
3. Pharmacophore mapping
In this type of screening, the approach is to identify lead compounds against target. Pharmacophore can be described as a 3-dimensional arrangement of the functional groups in the molecular framework which is important for the binding of an active site or macromolecule.
4. Quantitative Structure Activity Relationship (QSAR)
It refers to a method which relates structural features of a molecule to any biological activity in the quantitative term. This QSAR analysis is used to make the linear bond between selected structural features in series of any related molecule and their known activity level.
Qualities of a Lead
A compound to be considered as a lead should possess following qualities:
- Potency: It should have the potency or the ability to modulate any target with high degree of effectiveness.
- Solubility: It should have high solubility in water.
- Metabolic stability: The compound should be metabolically stable
- Lipophilicity: It should possess a mild lipophilicity which would help it to penetrate through plasma membrane.
- Toxicity: It must be less toxic.
Lead Optimization and Clinical Trials
After assessing initial candidate drug(s) for the quality, they are optimized and then after registration of that compound as investigational new drug, it is sent for clinical trials which have following stages:
- Pre-clinical Phase
- Animal Tests
- Phase 1: Healthy (Normal) Human Volunteers
- Phase 2: Safety and efficacy evaluation in patients
- Phase 3: Large sample study
- Phase 4: Long term monitoring