Drug Discovery Process

• Drug discovery is the initial phase in developing drug.
• Drug discovery identifies molecules or compounds that interact with a target in the body to treat or manage disease.
• The process focuses on New Chemical Entities (NCEs) that have been newly synthesized and not previously used as drugs.
• Drug discovery also focuses on Biological Drugs like monoclonal antibodies, peptides, or gene therapies that target specific disease pathways.

Steps in Drug Discovery

• Target identification is the first step to identify and validate a biological target involved in the disease process.
• Targets can be a protein, enzyme, ion channel, or receptor that can alter the disease outcome when modulated.
• Researchers use genomic, proteomic, and biochemical studies to find biological components associated with the disease.
• ACE inhibitors that treat hypertension work by inhibiting the angiotensin-converting enzyme (ACE).
• In diabetes, drugs like DPP-4 inhibitors target the enzyme dipeptidyl peptidase-4 to regulate blood sugar levels.
• After identifying the target, experiments confirm its role in the disease process using genetic knockdown or small molecule inhibition mehtods.
• Hit identification finds molecules (hits) that bind to the identified target and show biological activity through High-Throughput Screening (HTS).
• Scientists test millions of chemical compounds rapidly to see compound interactions with the target.
• HTS utilizes automated robotic systems to screen large compound libraries.
• A hit is any molecule that shows initial binding activity with the target but may not yet have the potency or safety.

Other sources of hit compounds

• Natural products (e.g., plant extracts)
• Synthetic compound libraries
• Fragment-based drug discovery combines small chemical fragments to form larger molecules with higher binding affinity

Lead Optimization

• The objective is to chemically modify the hits to enhance their potency, specificity, and stability, while minimizing toxicity.
• Scientists modify the chemical structure of hit compounds to produce more effective lead compounds.
• The goal is to create a molecule with stronger activity against the target.
• Increased selectivity is achieved through reduced interaction with off-target molecules, which minimizes side effects.
• Compounds should have better stability through Longer shelf life and favorable pharmacokinetic properties.

Computational Drug Design

• Molecular docking techniques simulate how a molecule fits into the target's active site.
• This process predicts how well a lead compound will bind to the target and suggests modifications for improvement.
• Medicinal chemistry involves iterative chemical synthesis and testing to develop an optimized drug candidate.

In Vitro Testing

• Confirms the activity of optimized leads at the cellular level and assesses their toxicity.
• Lead compounds are tested on cell cultures (in vitro) to ensure they work on human-like cells and produce the desired biological effect.
• Cancer drugs are tested on tumor cell lines to see if they inhibit growth.
• Efficacy is assessed to determine whether the compound successfully engages the target and produces the expected biological response.
• Toxicity is assessed early to avoid harmful effects in animal or human testing via evaluating cytotoxicity.
• Selectivity ensures that the compound selectively interacts with the intended target without affecting unrelated pathways.