Lesson 1. Introduction to Drug Discovery and Development

Folklore and Serendipity

SOURCES OF DRUGS:

• simply from tales or stories, or in the case of some scientists, out of chance and luck (very rare)

Serendipity

SOURCES OF DRUGS:

Folklore and Serendipity

• out-of-chance or out-of-luck discoveries

Staphylococcus bacterium

SOURCES OF DRUGS:

Folklore and Serendipity Examples:

1. Alexander Fleming left a ______________________ in a petri dish that bred antibacterial fungi

2. Even ___________ discovered treatment through luck

1 = ?

albularyos

SOURCES OF DRUGS:

Folklore and Serendipity Examples:

1. Alexander Fleming left a ______________________ in a petri dish that bred antibacterial fungi

2. Even ___________ discovered treatment through luck

2 = ?

Herbal Plants

SOURCES OF DRUGS:

Folklore and Serendipity

• _____________ are a basis for fidelity (faith) if unique; often used in ethnopharmacies. If albularyos use them, maybe it is effective, which can give way for scientists to have “faith” in further studying them.

mud or crushed leaves

SOURCES OF DRUGS:

Folklore and Serendipity

1. First effective drugs were probably simple external preparations like _____________________.

2. This is developed into __________________, which contain a mixture of many potentially active or potent molecules/compounds.

1 = ?

crude extracts

SOURCES OF DRUGS:

Folklore and Serendipity

1. First effective drugs were probably simple external preparations like _____________________.

2. This is developed into __________________, which contain a mixture of many potentially active or potent molecules/compounds.

2 = ?

Rational or Scientific

SOURCES OF DRUGS:

• gradually evolved with important advances in chemistry and physiology that gave rise to the new science of pharmacology

pure compounds

SOURCES OF DRUGS:

Rational or Scientific

• often requires _________________ for proper drug testing

Drug Repurposing

SOURCES OF DRUGS:

Rational or Scientific

• using an approved drug that already has a known treatment for something new

Minoxidil

SOURCES OF DRUGS:

Rational or Scientific — Drug Repurposing

• It was initially used for hypertension but was repurposed to treat alopecia

• Since it is an antihypertensive drug, when it dilates the blood vessels, it allows more blood flow to the scalp letting more nutrients and hormones for hair growth

target protein

SOURCES OF DRUGS:

Rational or Scientific

• In isolation, the compound isolated must be matched with its a._______________ and the b.__________________ must be explained.

a = ?

mechanism of action

SOURCES OF DRUGS:

Rational or Scientific

• In isolation, the compound isolated must be matched with its a._______________ and the b.__________________ must be explained.

b = ?

Salicin

SOURCES OF DRUGS:

Rational or Scientific — Isolated Compounds

1. An isolated alcohol glycoside from Willow bark (Salix purpurea), _________, is an anti-inflammatory compound.

2. It is hydrolyzed and oxidized which becomes __________________ which has anti-fungal properties.

3. It undergoes acetylation which becomes _______________________, an anti-inflammatory compound.

1 = ?

Salicylic Acid

SOURCES OF DRUGS:

Rational or Scientific — Isolated Compounds

1. An isolated alcohol glycoside from Willow bark (Salix purpurea), _________, is an anti-inflammatory compound.

2. It is hydrolyzed and oxidized which becomes __________________ which has anti-fungal properties.

3. It undergoes acetylation which becomes _______________________, an anti-inflammatory compound.

2 = ?

Acetylsalicylic Acid (APA)

SOURCES OF DRUGS:

Rational or Scientific — Isolated Compounds

1. An isolated alcohol glycoside from Willow bark (Salix purpurea), _________, is an anti-inflammatory compound.

2. It is hydrolyzed and oxidized which becomes __________________ which has anti-fungal properties.

3. It undergoes acetylation which becomes _______________________, an anti-inflammatory compound.

3 = ?

sustainability

SOURCES OF DRUGS:

Rational or Scientific — Isolated Compounds

Why not just use salicin, which already has anti-inflammatory effects?

• Because of a.__________________.

• Many of the b.___________________________, which contained anti-cancer components, were killed and harvested to create Paclitaxel (Taxol ® ).

• If we were to do the same with Willow bark (which contains very little salicin), _____________________ as well.

• Hence, instead of using salicin, scientists __________________________ in the lab from easy-to-obtain chemicals without relying too much on naturally produced salicin.

a = ?

Pacific Yew trees (Taxus brevifola)

SOURCES OF DRUGS:

Rational or Scientific — Isolated Compounds

Why not just use salicin, which already has anti-inflammatory effects?

• Because of a.__________________.

• Many of the b.___________________________, which contained anti-cancer components, were killed and harvested to create Paclitaxel (Taxol ® ).

• If we were to do the same with Willow bark (which contains very little salicin), _____________________ as well.

• Hence, instead of using salicin, scientists __________________________ in the lab from easy-to-obtain chemicals without relying too much on naturally produced salicin.

b = ?

resources would deplete

SOURCES OF DRUGS:

Rational or Scientific — Isolated Compounds

Why not just use salicin, which already has anti-inflammatory effects?

• Because of a.__________________.

• Many of the b.___________________________, which contained anti-cancer components, were killed and harvested to create Paclitaxel (Taxol ® ).

• If we were to do the same with Willow bark (which contains very little salicin), _____________________ as well.

• Hence, instead of using salicin, scientists __________________________ in the lab from easy-to-obtain chemicals without relying too much on naturally produced salicin.

c = ?

synthesize aspirin cheaply and quickly

SOURCES OF DRUGS:

Rational or Scientific — Isolated Compounds

Why not just use salicin, which already has anti-inflammatory effects?

• Because of a.__________________.

• Many of the b.___________________________, which contained anti-cancer components, were killed and harvested to create Paclitaxel (Taxol ® ).

• If we were to do the same with Willow bark (which contains very little salicin), _____________________ as well.

• Hence, instead of using salicin, scientists __________________________ in the lab from easy-to-obtain chemicals without relying too much on naturally produced salicin.

d = ?

Drug Product Track

SOURCES OF DRUGS:

2 Tracks of DOST DDD:

• A pure compound itself is used to make a drug and is the generic name

acetylsalicylic acid

SOURCES OF DRUGS:

2 Tracks of DOST DDD:

• example of Drug Product Track

Herbal Product Track

SOURCES OF DRUGS:

2 Tracks of DOST DDD:

• the standardized crude extract is used, which contains an “interplay” of compounds

• it contains multiple active constituents that work with each other to produce an effect rather than one isolated compound doing it

• purifying and isolating the compound is expensive and time-consuming

Lagundi (Vitex negundo) and Sambong (Blumea balsamifera)

SOURCES OF DRUGS:

2 Tracks of DOST DDD:

• examples of Herbal Product Track

1950s

SOURCES OF DRUGS:

• Until the ______, most of the pharmacopeia consisted of natural products such as Penicillin.

interacting with selected drug targets

SOURCES OF DRUGS:

• Assumed that highly eveolved biomolecules stand a better chance of ___________________________________ than synthetics

Highly Evolved Biomolecules

SOURCES OF DRUGS:

• large compounds like proteins or natural products produced by microorganisms and plants that are difficult to synthesize in the lab

Insulin, Eltroxin, Peptides, and Monoclonal antibodies

SOURCES OF DRUGS:

• Examples of highly evolved biomolecules

golden age of drugs

SOURCES OF DRUGS:

• After the 1950’s, the golden age of organic chemistry yielded the a._________________

• Until now, b.___________________ dominates the market.

• c.____________________ are now fairly routine, but are often difficult and time-consuming.

• The dawn of d.________________ in the market has just started.

a = ?

small synthetic drugs

SOURCES OF DRUGS:

• After the 1950’s, the golden age of organic chemistry yielded the a._________________

• Until now, b.___________________ dominates the market.

• c.____________________ are now fairly routine, but are often difficult and time-consuming.

• The dawn of d.________________ in the market has just started.

b = ?

Purification and Structure Determination

SOURCES OF DRUGS:

• After the 1950’s, the golden age of organic chemistry yielded the a._________________

• Until now, b.___________________ dominates the market.

• c.____________________ are now fairly routine, but are often difficult and time-consuming.

• The dawn of d.________________ in the market has just started.

c = ?

biomolecules

SOURCES OF DRUGS:

• After the 1950’s, the golden age of organic chemistry yielded the a._________________

• Until now, b.___________________ dominates the market.

• c.____________________ are now fairly routine, but are often difficult and time-consuming.

• The dawn of d.________________ in the market has just started.

d = ?

bacteria

SOURCES OF DRUGS:

• Biomolecules are highly evolved molecules derived from __________

marine sediments

SOURCES OF DRUGS:

Biomolecules

• Dr. Dalisay discovered antibiotics from a._______________

• b._____________________ are a group of bacteria under the genus Streptomyces spp.

• This genus produces many antimicrobials like c.____________ from Ilo-ilo.

• The bacteria that Dr. Dalisay discovered will prepare their own compounds to survive and kill other bacteria to d.__________________________, and when isolated and studied further, they can be used as antibiotics by humans.

a = ?

Actinomyces

SOURCES OF DRUGS:

Biomolecules

• Dr. Dalisay discovered antibiotics from a._______________

• b._____________________ are a group of bacteria under the genus Streptomyces spp.

• This genus produces many antimicrobials like c.____________ from Ilo-ilo.

• The bacteria that Dr. Dalisay discovered will prepare their own compounds to survive and kill other bacteria to d.__________________________, and when isolated and studied further, they can be used as antibiotics by humans.

b = ?

erythromycin

SOURCES OF DRUGS:

Biomolecules

• Dr. Dalisay discovered antibiotics from a._______________

• b._____________________ are a group of bacteria under the genus Streptomyces spp.

• This genus produces many antimicrobials like c.____________ from Ilo-ilo.

• The bacteria that Dr. Dalisay discovered will prepare their own compounds to survive and kill other bacteria to d.__________________________, and when isolated and studied further, they can be used as antibiotics by humans.

c = ?

compete for nutrients and space

SOURCES OF DRUGS:

Biomolecules

• Dr. Dalisay discovered antibiotics from a._______________

• b._____________________ are a group of bacteria under the genus Streptomyces spp.

• This genus produces many antimicrobials like c.____________ from Ilo-ilo.

• The bacteria that Dr. Dalisay discovered will prepare their own compounds to survive and kill other bacteria to d.__________________________, and when isolated and studied further, they can be used as antibiotics by humans.

d = ?

New Chemical Entity (NCE)

DIVERSITY OF DRUGS:

• drugs that are patented such as morphine and codeine

Natural

CLASSIFICATION OF DRUGS

By Origin

• extracted from plant, animal, or mineral sources

• ex: Opium Poppy (Papaver somniferum) with morphine as an active principle

Synthetic

CLASSIFICATION OF DRUGS

By Origin

• chemically structured in the lab

Small Molecules

CLASSIFICATION OF DRUGS

By Structure:

• small and low molecular weight of less than 500

• ex: water, glucose, oxygen, ethanol, amino acids, urea

Biomolecules/Macromolecules

CLASSIFICATION OF DRUGS

By Structure:

• generally much larger, high molecular weight, complex, and may consist of repeating units

• ex: proteins, DNA, RNA, and polysaccharide

Small Molecules

CLASSIFICATION OF DRUGS

By Size:

• involve organic/inorganic compounds with a MW less than 500

• almost all popular and conventional drugs

• some are natural products which have MW greater than 500

Biopharmaceuticals

CLASSIFICATION OF DRUGS

By Size:

• much larger, include peptides, nucleic acids and related polymers

• MW = tens of thousands

• arise from biotechnology

• rising in the last few decades

• ex: drugs for cancer and immuno diseases

Morphine

OPIUM POPPY:

1. Its pure drug compound is ___________ which is a central narcotic analgesic

2. If methylation, __________________ is produced which is an antitussive in cough syrups; insoluble in aq. NaOH.

3. If acetylation, ___________________ is produced which is more lipophilic than the pure drug compound that is why it is prohibited/illicit drug.

4. All of these forms are considered as _______________________.

1 = ?

codeine (methylmorphine)

OPIUM POPPY:

1. Its pure drug compound is ___________ which is a central narcotic analgesic

2. If methylation, __________________ is produced which is an antitussive in cough syrups; insoluble in aq. NaOH.

3. If acetylation, ___________________ is produced which is more lipophilic than the pure drug compound that is why it is prohibited/illicit drug.

4. All of these forms are considered as _______________________.

2 = ?

heroin (diacetylmorphine)

OPIUM POPPY:

1. Its pure drug compound is ___________ which is a central narcotic analgesic

2. If methylation, __________________ is produced which is an antitussive in cough syrups; insoluble in aq. NaOH.

3. If acetylation, ___________________ is produced which is more lipophilic than the pure drug compound that is why it is prohibited/illicit drug.

4. All of these forms are considered as _______________________.

3 = ?

isoquinolines

OPIUM POPPY:

1. Its pure drug compound is ___________ which is a central narcotic analgesic

2. If methylation, __________________ is produced which is an antitussive in cough syrups; insoluble in aq. NaOH.

3. If acetylation, ___________________ is produced which is more lipophilic than the pure drug compound that is why it is prohibited/illicit drug.

4. All of these forms are considered as _______________________.

4 = ?

apomorphine

OPIUM POPPY:

• Dehydrated form of morphine is a.________________, which is a central emetic agent which stimulates the chemoreceptor zone of the brain or the vomiting center.

• This is different from b.____________________________ which is a local emetic agent.

a = ?

Ipecac syrup (Cephaelis ipecacuanha)

OPIUM POPPY:

• Dehydrated form of morphine is a.________________, which is a central emetic agent which stimulates the chemoreceptor zone of the brain or the vomiting center.

• This is different from b.____________________________ which is a local emetic agent.

b = ?

enzymes and substrates

NATURE OF DRUGS:

• Greatly resembles _____________________ on many levels.

binding of the ligand and drug target

NATURE OF DRUGS:

• In drug discovery, the main goal at molecular level is _______________________.

activators (agonist) or inhibitors (antagonist)

NATURE OF DRUGS:

• Drugs may be _____________________________ that can target a particular receptor.

Isomers

NATURE OF DRUGS:

• ________ of similar compounds can spell marked differences in their effects and uses.

Polarity and Geometry

NATURE OF DRUGS:

• important properties which influence binding:

agonist

NATURE OF DRUGS:

Agonist and Antagonist

• If there is an intrinsic effect then it is an a.______________

• If there is no intrinsic effect then it is an b.______________

a = ?

antagonist

NATURE OF DRUGS:

Agonist and Antagonist

• If there is an intrinsic effect then it is an a.______________

• If there is no intrinsic effect then it is an b.______________

b = ?

Polarity

NATURE OF DRUGS

• impacts ionization and controls balance between hydrophilicity/lipophilicity

• determines the drug’s solubility

Solutions and Syrups

SOLUBILITY IN DOSAGE FORMS:

1. _______________________ if the drug is water soluble

2. _______________________ if the drug is lipid soluble

1 = ?

use cosolvents, suspensions, and emulsions

SOLUBILITY IN DOSAGE FORMS:

1. _______________________ if the drug is water soluble

2. _______________________ if the drug is lipid soluble

2 = ?

Disintegration

DISTRIBUTION IN THE BODY:

1. depends on the formulation of the drug and its excipients

2. requires the drug to be water-soluble in order to travel in the bloodstream

3. requires the drug to be lipid-soluble to diffuse across the cell membrane of the target tissue or organ

1 = ?

Dissolution

DISTRIBUTION IN THE BODY:

1. depends on the formulation of the drug and its excipients

2. requires the drug to be water-soluble in order to travel in the bloodstream

3. requires the drug to be lipid-soluble to diffuse across the cell membrane of the target tissue or organ

2 = ?

Absorption

DISTRIBUTION IN THE BODY:

1. depends on the formulation of the drug and its excipients

2. requires the drug to be water-soluble in order to travel in the bloodstream

3. requires the drug to be lipid-soluble to diffuse across the cell membrane of the target tissue or organ

3 = ?

Lysine, Arginine, Histidine

INTERMOLECULAR FORCES TO THE RECEPTORS:

• If your target protein is rich in glutamic and aspartic acid, the drug should be rich in __________________________ as opposite charges attract.

Strong Acidic and Basic Drugs

INTERMOLECULAR FORCES TO THE RECEPTORS:

• These drugs aid in dissolution as they are highly ionized, polar, and water-soluble but they are not capable of permeability.

Geometry

NATURE OF DRUG:

• impacts everything as the protein’s binding site should have a compatible drug that fits it both in size and shape

Receptors

NATURE OF DRUGS

Geometry

• If the drug is designed to target the __________, it can affect the pharmacodynamic properties.

• ex: beta blocker channels or calcium channel blockers

Metabolizing enzymes

NATURE OF DRUGS

Geometry

• If the drug is designed to target the __________, it can affect the pharmacokinetic parameters esp. elimination

Easson-Stedman Model

• shows the importance of drug chirality

• old model emphasizing that for your drug to bind, it needs to have at least three effective bonds for it to elicit pharmacodynamic and intrinsic effects

Active Enantiomer

EASSON-STEDMAN MODEL:

• fits all three sites perfectly for maximum biological response

Inactive Enantiomer

EASSON-STEDMAN MODEL:

• matches only two or one sites, resulting in low or no intrinsic activity

more negative energy

EASSON-STEDMAN MODEL:

• When comparing the active enantiomer to the inactive ones, the active enantiomer has a __________________ = more efficient binding = stronger

Root Mean Square Deviation (RMSD)

EASSON-STEDMAN MODEL:

• determines the accuracy of the position

• ideal value should be less than 2

Ibuprofen

CHIRAL RESOLUTION

• one is more potent

Quinine and Quinidine

CHIRAL RESOLUTION

• both have very different uses

Cisplatin and Transplatin

CHIRAL RESOLUTION

• one has activity, and one has none

Thalidomide

CHIRAL RESOLUTION

• One has activity and one is toxic

1-6 years

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

1. for drugs that requires a lot of tests (ex: vaccines and oral tablets)

2. requires less tests (ex: ointments)

1 = ?

1-3 years

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

1. for drugs that requires a lot of tests (ex: vaccines and oral tablets)

2. requires less tests (ex: ointments)

2 = ?

Idea

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

• general subject or therapeutic concept

Basic Research

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

• majority of the research at this stage is publicly funded at universities, colleges, and independent research institutions in every state

• goal is pre-formulation: understand your drug and determine its characterization and physicochemical properties

• includes medicinal organic chemistry, including TLC, color reactions, alkaloid isolation, in vitro, in silico testing, etc.

Cell-based Assay

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Basic Research — In Vitro Testing

• uses cell lines to measure responses to drugs, cytotoxicity testing, and safety

• used for cytotoxicity testing

Enzyme-Based Assay

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Basic Research — In Vitro Testing

• tracks how fast an enzyme changes a specific substance into a new product

• ex: ELISA kits

Applied Research

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Development

• known as formulation

• design and develop the formulation based on the disease and drug

Clinical Trials

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Development

• once a disease target is identified, drugs are designed and tested that can both be publicly and privately funded research

• includes pharmaceutical chemistry and pharmaceutics

Phase I

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Clinical Trials

• Is it safe?

• uses a small size of healthy people

Phase II

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Clinical Trials

• Does it work?

• uses a quite large amount of patients with disease

Phase III

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Clinical Trials

• Does it really work?

• Is it better than the drugs we have?

• uses a large amount of patients with disease

Regulatory Approval

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Delivery

• includes Pharmaceutical Chemistry

• human trials are completed

• needs FDA approval

• safety and evaluation continue after approvals

Patient Care

DRUG DISCOVERY AND DEVELOPMENT PIPELINE:

Delivery

• includes practice of pharmacy