From Target identification to Lead optimization

Project factors to consider

Medical need, opportunity, scientific feasibility, cost and risk, potential. Assessment includes, market analysis, competitive assessment.

What is market analysis

Examine, size of potential population, disease characteristics (rarity, acute, chronic), cost, safety, effectiveness, convenience, reimbursement.

Competitive assessment, what makes different times entering the market better

is it worth competing. Are you first to the market. Being second in the market offers opportunity like, efficacy, safety, lower cost or better access, more convenient nose or administration.

Scientific feasibility

Is the disease well understood, is it solvable, is the mechanism understood, can it be treated, are biochemical tools available, are there existing drugs, or patents, or research.

What is HTS

Rapid automated testing of compounds, tests hundreds of thousands of compounds in a large library filled with previously synthesized products, natural products, external products. Compounds that show the desired effect are hits.

Why is it important to test a variety of compounds

Increases potential hits, drug target interactions or activity may be difficult to predict.

What is the first initial step of HTS

Compounds are screened under standardized conditions, with a predefined activity threshold, may product hundreds of hits then retested to confirm activity, and checked for nonspecific activity or interference.

HTS false positives

False positives may happen due to impurities, decomposition, nonspecific reactivity, aggregation, interference, poor solubility. Must be retested to confirm try activity, or any misleading activity

What are pains

Pan-assay interference compounds. They alert molecules that may show up positive for any number of reasons, they are warning signs not automatic proof of a false positive, you must retest the alerted compounds

How does retesting hits work

You retested them with fresh samples, make sure the activity is reproducible , test at different concentrations, determine the compound response relationship, the more active the compound the greater effect as concentration increases up to a maximum response.

What is used to confirm the chemical structure of hits

You must confirm the identity and purity of proposing hits, using nmr spectroscopy to confirm structure of a molecule, and mass spectrometry to confirm the mass to charge ratio in molecules. Test structurally related compounds because sometimes similar structures act the same way, identify which feature in the structure affects the target.

Examples of drugs developed by HTS

Nevirapine, Gleevec, Quinolones

What are natural products

Products obtained by living organisms, plants microorganisms, animals. They provide biologically active compounds and starting points for drug discovery.

What are secondary metabolites

Compounds that are not directly involved in core growth and reproduction, stuff for défense, competition, attraction, environmental interaction. Often biologically active so a good point to look at for drugs.

How do you find natural products and what are the challenges

Obtain the sample from a biological source and prepare and screen for activity. Isolate active compounds and determine chemical structure. These active compounds may occur in very small amounts, so would be hard to find isolate and purify. The structures may be very complex. So synthesis and modification would be challenging. You must consider if the product is able to be made or semi made, so it may be acheviable long term

Examples of natural product drugs

Penicillin, Paclitaxel, Digoxin

Spongistatin example

A drug that was created from a natural product and has extremely potent anti tumour activity, but a very large amount is needed for a small amount of drug. So there must be an alternative scalable source to develop it further.

Rational drug design

This pathway uses existing knowledge to design a new drug. The information may come from enzyme substrates, natural inhibitors, receptor ligands, existing drugs, target knowledge.

Rationally designed drug examples

Captopril, acyclovir, (using one drug previously made and taking its active ingredient and changing it so it works in a different way) indinavir.

Combinatorial chemistry pathway