[01-MIDTERMS-MEDORG] DRUG DISCOVERY

Discovery Phase

This includes synthesis, isolation, fermentation, screening, and SAR studies.

• Synthesis

• Isolation

• Fermentation

• Screening

• SAR studies

Discovery phase includes?

Choosing a disease

Discovery Phase:

Focus is on the financial return.

Financial return

Choosing a disease, the focus is on the?

Choosing a drug target

Discovery Phase:

• Receptor (agonist, antagonist, partial antagonist)

• Enzymes (inducer, inhibitor)

• Nucleic acid

• Agonist

• Antagonist

• Partial antagonist

What are the different types of receptor ligand?

• Inducer

• Inhibitor

Enzymes can act as?

Finding the drug first

When choosing a drug target, it depends on?

Chemical messenger

The discovery of this messenger triggers the physiological changes at cellular level.

• Proliferation

• Differentiation

• Migration

• Survival

• Apoptosis

• Depolarization

What are the cellular level/process?

Genome projects

An increasing number of new receptor and enzymes — potential drug targets.

New receptors and enzymes

What are the potential drug targets because of genome projects?

Human Genome Project (HGP)

Ambitious research at deciphering the chemical make-up of entire human genetic code.

• In vivo test

• In vitro test

In identifying a bioassay, what tests are used?

In vivo test

Identifying a Bioassay:

Inducing a clinical condition and treated with the test drug (inside — use test samples).

In vitro test

Identifying a Bioassay:

Drugs activity is tested on isolated tissues, cells, or enzymes (involves studying microorganism, human or animal cell).

Desired pharmacological property

A compound showing this property which can be used to initiate a medicinal chemistry project.

1. Screening of natural products

2. Medicinal folklore

3. Screening synthetic banks

4. Combinatorial synthesis

5. Computer-aided design (CAD)

6. Serendipity and prepared mind

7. Use of Nuclear Magnetic Resonance (NMR)

8. Existing drugs

What are the eight (8) ways of discovering a lead compound?

1. Morphine

2. Cocaine

3. Quinine

4. Periwinkle

5. Reserpine

6. Paclitaxel

What are the six (6) natural products in plant kingdom?

Papaver somniferum

Plant Kingdom: Natural Products

What is the source plant of morphine?

Opium poppy

Papaver somniferum is commonly known as?

Papaver somniferum

What is the scientific name of opium poppy?

Erythroxylum coca

Plant Kingdom: Natural Products

What is the source plant of cocaine?

Coca

Erythroxylum coca is commonly known as?

Erythroxylum coca

What is the scientific name of coca?

Cinchona tree

Plant Kingdom: Natural Products

What is the source plant of quinine?

Quinine

This is an anti-malarial drug.

Catharanthus roseus

Plant Kingdom: Natural Products

What is the source plant of vincristine and vinblastine?

Madagascar Periwinkle

Catharanthus roseus is commonly known as?

Catharanthus roseus

What is the scientific name of periwinkle?

Vinca species

Periwinkle (Catharanthus roseus) is formerly classified as what species?

Rauvolfia serpentina

Plant Kingdom: Natural Products

What is the source plant of reserpine?

• Indian snakeroot

• Devil pepper

Rauvolfia serperntina is commonly known as?

Rauvolfia serpentina

What is the scientific name of Indian snakeroot or devil pepper?

Reserpine

This is an anti-hypertensive drug.

Taxus brevifolia

What is the source plant of paclitaxel?

Pacific Yew Tree

Taxus brevifolia is commonly known as?

Penicillium notatum

Microbiological World:

What is the producing microorganism of penicillin?

Penicillium notatum

A mold that produces the antibiotic penicillin.

Cephalosporium acremonium

Microbiological World:

What is the producing microorganism of cephalosphorin?

Cephalosporium acremonium

A fungus that produces cephalosporin antibiotics.

Streptomyces genus

Microbiological World:

What is the producing microorganism of tetracyclines?

Streptomyces genus

A group of bacteria that produce many important antibiotics (e.g., streptomycin).

Actinomycetes

Microbiological World:

What is the producing microorganism of aminoglycosides?

Actinomycetes

Filamentous bacteria that are major sources of antibiotics.

Aspergillus species

Microbiological World:

What is the producing microorganism of lovastatin?

Aspergillus species

Molds that produce various medicinal and industrial compounds.

• Mushroom

• Oyster mushroom

• Red yeast rice

What are some examples of Aspergillus species?

Red yeast rice

Rice fermented from Monascus purpureus.

Monacolin K

This is the active compound produced by Monascus purpureus.

• Proteins

• Polysaccharides bile acids

• Estrogens

What are the natural products from animal sources?

• Somatostatin

• Glucagon

Animal Sources:

What are some examples of proteins?

Heparin

Animal Sources:

What is an example of polysaccharide?

Polysaccharide bile acids

From porcine mucosa and bovine lungs, traditionally been extracted from pig intestines and cattle lungs.

• Porcine mucosa

• Bovine lungs

Polysaccharide bile acids is from?

• Pig intestines

• Cattle lungs

Polysaccharides (heparin) bile acids is traditionally extracted from what organ of pig and cattle?

Estrogen

This hormone is obtained from the urine of pregnant mare.

Mare

A female horse is called?

Vaccines

Biological Source:

Living or killed microorganisms.

Screening of natural products

Ways of Discovering a Lead Compound:

The systematic testing of compounds from plants, animals, or microorganisms to identify potential therapeutic activity.

Medical folklore

Ways of Discovering a Lead Compound:

Traditional knowledge and practices about disease treatment passed down through cultures and generations.

Screening synthetic banks

Ways of Discovering a Lead Compound:

The evaluation of large libraries of chemically synthesized compounds for biological activity.

Combinatorial synthesis

Ways of Discovering a Lead Compound:

Uses chemical synthesis methods that make it possible to prepare large number of the composition in a single process.

Combinatorial chemistry

It includes strategies that allows identification for useful components of libraries for such large scale synthesis.

Computer-aided Design (CAD)

Ways of Discovering a Lead Compound:

The use of computational tools to model, design, and optimize drug molecules.

Serendipity and prepared mind

Ways of Discovering a Lead Compound:

The discovery of drugs by chance, recognized through scientific insight and prior knowledge.

Serendipity

Discovering something you weren’t looking for happens when you open your eyes to the unexpected.

Use of Nuclear Magnetic Resonance (NMR)

Ways of Discovering a Lead Compound:

Ability to directly observe chemical compounds and target the biomolecules. Used for ligand based and protein based approaches.

Existing drugs

Ways of Discovering a Lead Compound:

A popular term for a generic drug with an identical formulation and stated indications as a drug previously approved by the FDA.

1. 15,000 chemical compounds

2. 10-20 bioassay

High Throughput Screening is capable of examining (1)______ chemical compounds a week using (2)______ bioassay.

High Throughput Screening

Commonly used as automated equipment to rapidly test 1000 to millions of samples for biological activity at the model organism for cellular pathway or molecular level.

Me-too drugs

A pharmacologically active compound that is structurally related to a first-in-class compound, regarded as belonging to the same therapeutic class as the original compound, and used for the same therapeutic purposes, but which may differ in some respects, such as specificity of pharmacological action, adverse reactions profile, or drug–drug interactions.

• Ampicillin

• Aminopenicillin

What are the two (2) examples of me-too drugs?

• Tricyclic anti-depressants (TCAs)

• Beta blockers

• Instatives

These illustrates diversity for me-too drugs.

C₁₇H₁₉N₃O₃S

What is the chemical formula of esomeprazole and omeprazole?

Nexium

What is the brand name of Esomeprazole?

1

How many isomer for Esomeprazole?

Prilosec

What is the brand name of Omeprazole?

2

How many isomers for Omeprazole?

Claritin

What is the brand name of Loratadine?

Clarinex

What is the brand name of Desloratadine?

Celexa

What is the brand name of Citalopram?

Lexapro

What is the brand name of Escitalopram?

• NMR (functional groups)

• IR spectroscopy

• X-ray crystallography

• LC-MS

In new drug development process, these are used in determining the structure.

Critical tests

This tests is to avoid double hits to identify the chemical agent that is already known for its structure and chemical action.

Determining the structure

This is the most time-consuming process in new drug discovery.

Liquid chromatography-mass spectrometry

This is usually used as a liquid mixture for separation in?

Pharmacophore

Atom and functional groups required for a specific pharmacological activity, and their relative positions in space.

Pharmacophore

Ensemble of stearic and electronic features that is necessary to ensure the optical supramolecular interaction with the specific biological target and to trigger or block its biological response.

Pharmacology

Pre-clinical Studies:

The science of the properties of the drugs and its effects in the body (side effects, adverse drug reaction, mechanism of action).

Pharmacodynamics

Pre-clinical Studies:

The study of the interaction of drugs with cells.

Pharmacokinetics

Pre-clinical Studies:

The handling of a drug within the body, it includes the ADME processes.

Toxicity Testing

Pre-clinical Studies:

In vitro and in vivo testing, determination of LD 50.

Pharmaceutics

Pre-clinical Studies:

The general area of study concerned with the formulation, manufacturing, stability and effectiveness of a pharmaceutical dosage form.

In vivo and in vivo laboratory animal testing

During Pre-Clinical Drug Development:

A sponsor evaluates the drug’s toxic and pharmacologic effects through?

Genotoxicity Screening

During Pre-Clinical Drug Development:

This screening is performed, as well as investigations on drug absorption and metabolism, the toxicity of the drug's metabolites, and the speed with which the drug and its metabolites are excreted from the body.

Investigational New Drug Application

This is filed before drug may be given to human (clinical trials).

Orphan Drug

This is used to treat orphan disease, or disease that affects fewer than 200,000 people in the US (chronic lymphocytic leukemia, Gaucher (go-SHAY) disease is the result of a buildup of certain fatty substances in certain organs, particularly your spleen and liver, cystic fibrosis).

30 days

The FDA will review the filed IND Application for how many days?

20-80

Carry Out Clinical Trial:

How many number of patient in phase I?