OUR LADY OF FATIMA UNIVERSITY

College of Pharmacy

TOPIC 1
DRUG DISCOVERY & DRUG DESIGN

PDDD 311
OVERVIEW

¡ The student must be oriented on the goals of

developing new drugs; from understanding a
disease to bringing a safe and effective new
treatment to patients.
UNIT OUTCOMES

At the end of the discussion, the student should be

able to:
¡ 1. To understand the principles of Drug Discovery
¡ 2. Understand and illustrate Drug design
 CHECKLIST

qRead course outcomes

qRead course guide prior to class attendance
qProactively participate in discussions
qWatch videos related to the topic
qParticipate in discussion board (Canvas)
qAnswer and submit course unit tasks
 REQUIRED READINGS
q Please read the following article thru the given link and journal.
q Drug discovery and development in [Link]
([Link]
[Link])
q Benjamin Blass. Basic Principles of Drug Discovery and
Development, Elsevier
q Ebook: Ansels’ Pharmaceutical Dosage Forms, 10th edition
q NOTE: This has been assigned to you by your instructor during the
previous meeting.
INTRODUCTION

It is the mission of pharmaceutical research

companies to take the path from understanding a
disease to bringing a safe and effective new
treatment to patients.
RESEARCHERS WORK TO:

• validate these targets

• discover the right molecule (potential drug) to interact with the
target chosen
• test the new compound in the lab and clinic for safety and
efficacy and
• gain approval and get the new drug into the hands of doctors
and patients.
And this whole process takes an average of 15 years
 DRUG DISCOVERY
The process of drug discovery involves the
identification of lead and its targets, synthesis,
characterization, screening, and assays for
therapeutic efficacy of lead.
Once a compound has shown its value , it will begin
the process of drug development prior to clinical
trails.
The average time required to bring a drug to
the market range from 12-15 years at an
average cost of $600 – 800 million.
Any drug development process must proceed
through several stages in order to produce a
product that is safe, efficacious, and has passed
all regulatory requirements.
STAGES OF DRUG DISCOVERY AND DEVELOPMENT
¡ The federal Food, Drug, and Cosmetic Act, as regulated by the U.S.
Code of Federal Regulations, requires a new drug to be approved
by the Food and Drug Administration (FDA)
before it may be legally introduced in the interstate commerce .
¡ The regulations apply to the drug products manufactured domestically
and those imported into the United States.
¡ Although these representations demonstrate the course for new
chemical entities (usually small molecule drugs), similar
developmental schemes are followed for new biological entities.
¡ After the discovery (e.g., synthesis) of a proposed new drug, the agent is
biologically characterized for pharmacologic and toxicologic effects and for
potential therapeutic application.

¡ Preformulation studies are initiated to define the physical and chemical

properties of the agent.

¡ Formulation studies follow to develop the initial features of the proposed

pharmaceutical product or dosage form.
¡ To obtain the required evidence demonstrating the drug’s safety
and effectiveness for its proposed use, a carefully designed and
progressive sequence of preclinical (e.g., cell culture, whole animal)
and clinical human) studies is undertaken.
PROCESS OF DRUG DISCOVERY
DRUG DISCOVERY

¡ Begins in the laboratory CHOOSE A

with scientists of various DISEASE!!
functional areas working
together to identify
cellular and genetic factors
that play a role in specific
disease
PRE-DISCOVERY

¡ Understanding the disease

¡ Know the underlying cause for the disease
¡ Try to understand how genes are altered – how they affect proteins they
encode
¡ How proteins interact with each other in living cells
¡ How those affected cells change the specific tissue they are in
¡ FINALLY, how the disease affect the entire patient
DRUG DISCOVERY

¡ Identification of target and resource

¡ STEPS
¡ Target Selection
¡ Target Identification
¡ Target Prioritization/ Validation
¡ Lead Identification
¡ Lead Optimization
 TARGET SELECTION

¡ Target selection in drug discovery is defined as the

decision to focus on finding an agent with a
particular biological action that is anticipated to
have therapeutic utility.
 TARGET SELECTION
¡ May be:
¡ TARGET: Naturally
¡ Protein molecule
existing cellular or
¡ A receptor
molecular structure
¡ Enzyme
involved in the disease
¡ Transport molecule
pathology on which the
¡ Ion channel
drug acts.
¡ Tubulin
¡ Immunophilin
 • Subject of • Have a
NEW

ESTABLISHED
discovery detailed
which include description of
proteins its functions
whose is in normal
discovered by pathology
function basis involved in
scientific human
research
TARGET IDENTIFICATION
Cellular and
¡ Scientists use a variety of genetic Targets
techniques to identify and
Genomics
isolate individual targets
to learn more about their Proteomics
functions and how they
influence disease. Bioinformatics
 ¡ Cellular and Genetic
¡ Genomics
Targets

¡ Involves identification of the target ¡ The study of genes and their

receptors or enzymes whereas for function
some biologic approaches the focus ¡ Exploit the findings from the
is at the gene or transcription level. sequencing of the human and other
¡ Drugs usually act on the targets, genomes to find new drug targets.
which are associated with disease. ¡ Based on 5 or 10 linked proteins
per gene, proposes that the number
of potential drug targets may lie
between 5,000 or 10,000
 ¡ Proteomics ¡ Bioinformatics

¡ It is also at the protein level that ¡ It plays a key role in various stages of
disease processes become manifest, the drug discovery process including
and at which most (91%) drugs act. ¡ target identification
¡ Therefore, the analysis of proteins ¡ computer screening of chemical
(including protein- protein, protein- compounds and
nucleic acid, and protein ligand
¡ Pharmacogenomics
interactions) will be utmost
importance to target discovery. ¡ Can compare the entire genome of
¡ Target identification with pathogenic and non-pathogenic strains
proteomics is performed by of a microbe and identify
comparing the protein expression genes/proteins associated with
levels in normal and diseased pathogenism
tissues.
 TARGET VALIDATION
¡ Involves demonstrating that a molecular target is critically
involved in a disease process and modulation of the target is
likely to have a therapeutic effect.
¡ Experimental approach by which a “potential” drug target can be
tested and given further credibility.
¡ Main Approach:
¡ Pharmacological
¡ Genetical
 Identify biological targets for the Ensure target is involved in disease
disease

• Target based approach identifies • In vitro tests performed to

genes and proteins involved in confirm that changing the target
disease. will result in a change in the
• Uses human genome disease
• Physiology based approach • In vivo tests performed with
identifies responses using cell animals to confirm in vitro tests.
based or animal model • Results will help predict profile of
• Individual or combination of new drugs and help determine if
approaches used. effective drugs can be made.
 LEAD IDENTIFICATION
¡ A lead compound or substance is one that is believed to have
potential to treat disease.
¡ Laboratory scientists can compare known substances with new
compounds to determine their likelihood of success.
¡ Leads are sometimes developed as collections, or libraries, of
individual molecules that possess properties needed in a new
drug.
¡ Testing is then done on each of these molecules to confirm its
effect on the drug
¡ Ways to find a lead compound
LEAD IDENTIFICATION
¡ Nature – bacteria, molds, plant extracts
¡ De Novo – scientists can also create molecules from scratch –
computer modeling
¡ High throughput screening – test thousands of compounds against
the target to identify any that might be promising
¡ Biotechnology – scientists can genetically engineer living systems
to produce disease-fighting biological molecules
 LEAD DISCOVERY
¡ Synthesis and Isolation
¡ Identification of small
¡ Separation of mixture
molecule modulators of
¡ Separation of impurities
protein function
¡ In vitro chemical synthesis
¡ The process of
¡ Biosynthetic intermediate
transforming these into
¡ Combinatorial Chemistry
high- content lead series.
¡ Assay Development
¡ High Throughput Screening
SYNTHESIS: APPROACHES FOR LEAD DISCOVERY

Serendipity:
¡ It is to follow when chance is very less. It has been the
historically the most successful way of discovering the drugs.
¡ E.g discovery of lavemisol,Vaproic acid.
SYNTHESIS: APPROACHES FOR LEAD DISCOVERY

Endogenous Source:
¡ Human disease arises from disturbance of the normal
biochemical processes. A logical therapeutic approach is the
administration of one or more of these naturally occurring
endogenous molecules or their analougues.
¡ The most important approach under this source is
Peptidomimetic Chemistry using non-peptides to mimic
endogenous peptide activity.
SYNTHESIS: APPROACHES FOR LEAD DISCOVERY

Exogenous Source: (Ethanobotany or

Ethanopharmacology)
¡ The molecules which are endogenous to the other life form
such as plants and animals but do not occur naturally within
human body,
¡ such molecules are classed as exogenous molecule for
prospective of drug designing for human beings
SYNTHESIS: APPROACHES FOR LEAD DISCOVERY

Rational Drug Design

¡ Approximately 2000 small molecules that theoretically exist in
our world out of which 1052 are drug like molecules and many
of which are purely synthetic and cannot occur naturally.
¡ Thus there is an opportunity to explore the none naturally
occurring synthetic compounds as potential source of lead
compound
COMBINATORIAL CHEMISTRY

¡ Rapid synthesis of or computer simulation of large no. of

different but structurally related molecules
¡ Search new leads
¡ Optimization of target affinity & selectivity.
¡ ADME properties
¡ Reduce toxicity and eliminate side effects
HIGH THROUGHPUT SCREENING
¡ It refers to the process by which pharmaceutical companies are
able to obtain initial screening data up to 1 million compounds
testing against as many as 50 different biological targets/years.
This expansion of data collection by several orders of
magnitude is primarily due to advancement in Robotics,
combinatorial chemistry and instrumentation.
¡ Screening of drug target against selection of chemicals.
¡ Identification of highly target specific compounds.
 SCREENING AND DESIGN

¡ SCREENING:
No intellectualization and
Investigation of a RANDOM assays

great number of
Also known as targeted/
compounds for a NON-RANDOM focused/ more narrow
approach
particular problem
or feature of them. CROSS
Whether the “hits” against the
chosen target will interfere
with other related targets.
PRIMARY HIT CONFIRMED HIT VALIDATED HIT
• Compound giving • Compound is • Confirmed hit that
positive result in a confirmed as positive shows selective
screening assay when assay is repeated activity

A Compound
HIT that passes such
a “screen”
ASSAY DEVELOPMENT

¡ Used for measuring the activity of a drug.

¡ Discriminate between compounds.
¡ Evaluate:
¡ Expressed protein targets.
¡ Enzyme/ substrate interactions.
 LEAD OPTIMIZATION
¡ Lead optimization compares the properties of various lead
compounds and provides information to help biopharmaceutical
companies select the compound or compounds with the
greatest potential to be developed into safe and effective
medicines.
¡ Often during this same stage of development, lead prioritization
studies are conducted in living organisms (in vivo) and in cells in
the test tube (in vitro) to compare various lead compounds and
how they are metabolized
¡ Optimization
¡ Alter the structure of lead candidates to improve properties
¡ can make it less likely to interact with other chemical pathways in
the body, thus reducing the potential for side effects
¡ “analogues” of the initial leads can be made and tested
¡ The biologists test the effects of analogues on biological systems
¡ Chemists take this information to make additional alterations that
are then retested by the biologists
¡ Early safety tests
¡ Lead compounds go through a series of tests to provide an early
assessment of the safety.
¡ Scientists test Absorption, Distribution, Metabolism, Excretion and
Toxicological (ADME/Tox) properties, or “pharmacokinetics,” of each
lead.
¡ Successful drugs must be:
¡ absorbed into the bloodstream,
¡ distributed to the proper site of action in the body,
¡ metabolized efficiently and effectively,
¡ successfully excreted from the body and o demonstrated to be not
toxic.
PRE-CLINICAL
¡ Conversion of drug candidate to a drug product for human clinical trials
¡ Lab and animal testing to determine if the drug is safe enough for human
testing.
¡ Testing the lead compounds extensively to determine if they should
move on to testing in humans
¡ Scientists carry out in vitro and in vivo tests.
¡ Scientists try to understand how the drug works and what its safety
profile looks like.
DRUG DESIGN
 DRUG DESIGN

¡ Drug design is the approach of finding drugs by design,

based on their biological targets.
¡ Typically a drug target is a key molecule involved in a
particular metabolic or signaling pathway that is specific to
a disease condition or pathology
FOUR TYPES OF DRUG DESIGN

1. Ligand-based drug design or Indirect Drug Design

2. Structure-based design or Direct Drug Design
3. Rational Drug Design
4. Computer-assisted Drug design
MECHANISM BASED DRUG DESIGN

¡ When the disease process is understood at the molecular level

and the target molecule(s) are defined
¡ Drugs can be designed specifically to interact with the target
molecule in such a way as to disrupt the disease.
STRUCTURE BASED DRUG DESIGN

¡ First techniques to be used in drug design.

¡ Helped in the discovery process of new drugs.
¡ Information about the structural dynamics and electronic
properties about ligands are obtained from calculations.
¡ Structure-based drug design can be divided roughly into two
categories:
I. Ligand based
II. Receptor Based
LIGAND-BASED DRUG DESIGN

¡ The first category is about “finding” ligands for a given receptor.

¡ A large number of potential ligand molecules are screened
¡ This method is usually referred as ligand-based drug design.
¡ It saves synthetic effort to obtain new lead compounds.
RECEPTOR-BASED DRUG DESIGN

¡ Another category is about “building” ligands, which is usually

referred as receptor-based drug design.
¡ Ligand molecules are built up within the constraints of the
binding pocket by assembling small pieces in a stepwise manner.
¡ These pieces can be either individual atoms or molecular
fragments.
¡ The key advantage of such a method is that novel structures,
not contained in any database, can be suggested
COMPUTER AIDED DRUG DESIGN
TECHNIQUES OF DRUG DESIGN
X-RAY CRYSTALLOGRAPHY
¡ Starting point for gathering
information from mechanistic drug
design.
¡ Determine structural information
about a molecule.
¡ Provides the critically important
coordinates needed for the
handling of data by computer
modeling system
TECHNIQUES OF DRUG DESIGN

NUCLEAR MAGNETIC
RESONANCE (NMR)
¡ NMR uses much softer radiation
¡ Examine molecules in the more mobile
liquid phase
¡ Three-dimensional information will be
obtained.
¡ Examines small molecule-macromolecule
complexes.
TECHNIQUES OF DRUG DESIGN

HOMOLOGY MODELING
¡ Homology modeling, also known as
comparative modeling of protein.
¡ Constructing an atomic-resolution model
of the "target" and an experimental three-
dimensional structure of a related
homologous protein.