Drug Discovery and Development Process
Research team formed
and objectives test Novel chemical synthesis
Chemicals tested for efficacy
and safety in test tubes and
animals. Results used to
choose drug candidate
Formulation, stability scale-
up synthesis, chronic safety
Drug application with FDA
Phase I, II, and III
FDA reviews NDADrug is approved for
• Drug design is an integrated developing discipline which
means era of ‘tailored drug’.
• It involves the study of effects of biologically active
compounds on the basis of molecular interactions in terms of
molecular structure or its physicochemical properties
• It studies the processes by which the drug produce their
effects, how they react with the protoplasm to elicit a
particular pharmacological effect or response how they are
modified or detoxified, metabolized or eliminated by the
• The biological activity may be “positive” as in drug design or
“negative” as in toxicology.
• Drug design involves either total innovation of a molecule or an
optimization of already available one.
• The drug is most commonly an organic small molecule that
activates or inhibits the function of a biomolecule such as a protein,
which in turn results in a therapeutic benefit to the patient.
• In the most basic sense, drug design involves the design of small
molecules that are complementary in shape and charge to the
biomolecular target with which they interact and therefore will bind
• Drug design frequently but not necessarily relies on computer
modelling techniques. This type of modelling is often referred to
as computer-aided drug design.
Pharmacokinetics of Drug Design
• Drugs must be polar - to be soluble in aqueous
conditions to interact with molecular targets
• Drugs must be ‘fatty’ - to cross cell
membranes to avoid rapid excretion
• Drugs must have both hydrophilic and
Traditional vs. Contemporary Approaches
Traditional vs. rational drug design
• Traditional is the origin of discovery from natural and accidental
• It was not targeted, but advancement in the pharmaceutical
sciences changed them to the systemized modern drug discovery.
• Traditional discoveries were through random discovery, trials,
ethnopharmacology, serendipity, and classical pharmacology
Examples of traditional approach, such as using cinchona bark
(quinine) to reduce fever, licorice roots in sore throats and stomach
ulcer, penicillin, etc.
Rational drug design
Developing molecules as a ligand either for targets
known the structure and function or the structural
information not known; however, it has predefined
properties and information can be taken from global
gene expression data.
Rational drug design
It can be divided in to
1. Ligand based drug design
b. Pharmacophore investigation
2. Structure based drug design
b. De novo drug design
• Once a promising drug target has been identified, researchers
aim to identify molecules that can interact with the target to
produce desired biological effects.
• A hit compound is a molecule that shows the desired type of
activity in a screening assay.
• It is important to develop pharmacologically relevant
screening assays for hit discovery and for the subsequent hit-
to-lead selection process.
• Lead compound is a prototype compound that has the desired
biological or pharmacological activity but may have many
• Providing lead compounds (via traditional medicines, natural
products, biological macromolecules, compound libraries,
computational chemistry, etc.)
• Lead compounds are selected from a collection of hits by refining
the screening criteria to enable the selection of the most promising
molecules for further development. The secondary assays
employed for lead selection may screen for off-target effects as well
as physicochemical and ADME (absorption, distribution,
metabolism and excretion) characteristics.
1. Where is the starting point of drug
2. What are the essential causes of the drugs
fail to reach the clinic?
3. What are the characteristics of good target?
4. What are the types of target?
Good target characteristics
• Plays a critical role in health-related issues
• Modulated without killing human or serious
• The structure of the target should be unique
• Well defined molecular structure of the target
• Modulate through designing small molecule
• Target sites are enzymes, receptors, ion channels, DNA,
RNA, proteins, viral surface proteins, etc.
• What are the most targets of the current drugs?
• Many experts believe that “without a well-validated
targets, pharmaceutical companies unable to maintain
current level of profitability” therefore, it’s one of the
stressing issues in the R&D.
• The process of the design of drugs typically involves
understanding the character of targets (e.g. enzyme, cell,
tissues, etc) related to the disease.
H to L LD and LO
Hit Lead Candidate
H to L: focus on target potency and selectivity; defined in
vitro properties profile.
LD: focus on identifying a novel compound with the
desired activity in vitro and vivo, with refinement of
LO: focus on fine tuning ADMET properties to identify one
or more preclinical development candidates.
Hit to Lead evolved in the 1990’s to address
a growing problem with drug candidate failures
• In the “old” days—
Ø Focus only on potency; SAR advancement emphasized
with minimal consideration of other attributes
Ø Result: compounds with poor bioavailability, high
clearance, high risk off-target effects, low solubility and low
dissolution properties, clinical trial failures
Ø Success rate of drug candidates from candidate nomination
to market: 4-6%
The modern day H to L process was developed to identify and
eliminate poor quality leads right up front
• Different screening strategies can be applied
3. Phenotypic screening
4. Computer Aided Drug Design
A. Structure-based drug design
B. Ligand-based drug design
C. Fragment screening
D. Virtual screening (Docking and Scoring)
1. The source of the hit
• Natural product leads tend to be structurally complex
2. The nature of the screening library
• Historical compound collections are a legacy of past discovery programs;
poorly managed DMSO solvated libraries may show considerable
3. The quality and precision of the screening method
• Noisy or low resolution screens introduce high false positives
4. The nature of the molecular target
• Molecular targets designed to interact with lipoidal ligands/substrates
tend to favor lipophilic hits; protein-protein interfaces favor structurally
complex (high MW) ligands
• Molecular weight (MW)
• Molecular volume and dimensions
• Calculated partition coefficient (clogP)
• Rotatable bonds
• Total polar surface area (tPSA)
• Aromatic rings
• Hydrogen bond donors and acceptors
• Physical properties influence the behavior of a compound in
the tissue and the effectiveness of the treatment
• Properties for most marketed drugs fall within a well-defined
range of values
• Lipinski’s ‘Rule of 5’ used to define potential drug candidates
Lipinski’s Rule of Fives
It also known as the Pfizer's rule of five or simply
the Rule of five (RO5) is a rule of thumb to evaluate
drug likeness or determine if a chemical compound
with a certain pharmacological or biological activity
has properties that would make it a likely orally
active drug in humans. The rule was formulated by
Christopher A. Lipinski in 1997, based on the
observation that most medication drugs are
relatively small and lipophilic molecules.
• The rule describes molecular properties important for
a drug's pharmacokinetics in the human body,
including their absorption, distribution, metabolism,
and excretion("ADME"). However, the rule does not
predict if a compound is pharmacologically active.
• The rule is important to keep in mind during drug
discovery when a pharmacologically active lead
structure is optimized step-wise to increase the activity
and selectivity of the compound as well as to insure
drug-like physicochemical properties are maintained as
described by Lipinski's rule. Candidate drugs that
conform to the RO5 tend to have lower attrition rates
during clinical trials and hence have an increased
chance of reaching the market
Components of the rule :
• Lipinski's rule states that, in general, an orally