Drug Design

Part-I

Dr. Nilesh Patel

M.Pharm, MBA, PhD
Assistant Professor
B. K. Mody Government Pharmacy
College, Rajkot
1 Drug Discovery
1. Choose a disease
2. Choose a drug target through genomics, proteomics
3. Identify a “bioassay”, bioassay = A test used to determine
biological activity.
4. Find a “lead compound”
5. Synthesize analogs of the lead
6. Identify Structure-Activity-Relationships (SAR’s)
7. Identify the “pharmacophore”
8. Optimize structure to improve interactions with target
9. Determine toxicity and efficacy in animal models.
10. Determine pharmacodynamics and pharmacokinetics of the
drug.
11. Patent the drug
12. Continue to study drug metabolism and test for toxicity
13. Design a manufacturing process
14. Carry out clinical trials
15. Market the drug
1. Drug Discovery
1.1 Discovery without Rational Design
1.2 Modern Rational Drug Design
2. Drug discovery process
2.1 Identification of biological targets
2.2 Validation of biological targets
2.3 Lead structure search
2.4 Lead optimization
2.5 Preclinical studies
2.6 Clinical trials
2.7 Formulations for clinical studies
3. Computer-aided drug design
3.1 Type of study Software
3.2 Protein-Ligand & Protein-Protein
docking
4. Molecular modeling and drug design
4.1 Molecular mechanics- force
4.2 Energy minimization methods
4.3 Conformational analysis
4.3.1 Systematic search
4.3.2 Monte Carlo simulation
4.3.4 Molecular dynamic simulationa
4.4 Structure-based and Ligand-
based drug design approaches
4.5 3D pharmacophore modeling
4.6 Rational drug design
4.6.1 Design of enzyme
inhibitors
4.6.2 De Novo Ligand design
5. Quantitative Structure Activity
Relationship (QSAR)
5.1 Parameters
5.1.1 Hydrophobicity
5.1.2 Electronic
5.1.3 Steric effects
5.2 Quantitative models
5.2.1 Hansch analysis
5.2.2 Free Wilson analysis
5.3 Other QSAR approaches like
HQSAR, CoMFA, CoMSIA
6. Combinatorial chemistry and High-
Throughput Screening (HTS)
1.1 Discovery without Rational Design
•Medicinal Chemistry Folklore
• Cinchona bark for chills and fevers
• Ephedra was used as a heart stimulant
• Opium poppy juice as an analgesic agent,
•Discovery of Penicillins
• John Burdon-Sanderson had done so in 1870, ironically
also at St. Mary’s Hospital in London, the same
institution where Fleming made the rediscovery In
1928
•Discovery of Librium
• first benzodiazepine tranquilizer drug, Librium
• Not quinazoline 3-oxide,but, rather, was the
benzodiazepine 4-oxide
•Discovery of Drugs through Metabolism Studies
Metabolite of terfenadine, fexofenadine was also found
to be a nonsedating antihistamine, but it can be
metabolized even in the presence of antifungal agents.
•Discovery of Drugs through Clinical Observations
• An antihistamine, dimenhydrinate was found also to
be effective in car sickness; a further study proved its
effectiveness in the treatment of seasickness and
airsickness. It then became the most widely used drug
for the treatment of all forms of motion sickness.
• Bupropion hydrochloride an antidepressant drug was
found to help patients stop smoking and became the
first drug marketed as a smoking cessation aid (Zyban).
1.2 Modern Rational Drug Design
 2. Drug discovery Process
The two principal origins of modern pharmaceutical
industries are apothecaries, which initiated
wholesale production of drugs in the mid-
nineteenth century, and dye and chemical
companies that were searching for medical
applications for their products in the late nineteenth
century
Merck, Hoffmann-La Roche, Wellcome, Abbott,
Smith Kline, Eli Lilly, also started as apothecaries in
the nineteenth century. Bayer, Ciba, Sandoz, and
Pfizer began as dye and chemical manufacturers.
 2.1 Identification of Targets

• Pharmaceutical companies will tend to avoid

products with a small market (i.e. a disease which
only affects a small subset of the population)
• Pharmaceutical companies will also avoid
products that would be consumed by individuals
of lower economic status (i.e. a disease which
only affects third world countries)
• Most research is carried out on diseases which
afflict “first world” countries: (e.g. cancer,
cardiovascular diseases, depression, diabetes, flu,
migraine, obesity).
 2.1 Identification Targets

• The Orphan Drug Act of 1983 was passed to

encourage pharmaceutical companies to develop
drugs to treat diseases which affect fewer than
200,000 people in the US
 2.1 Identification Targets
The majority of drugs exert their effects through
interactions with specific macromolecules in the
body. Many of these macromolecular drug targets
are proteins. You may recall that proteins are long
polymer chains of amino acid residues that can loop
and fold to produce grooves, cavities, and clefts that
are ideal sites for interactions with other large or
small molecules.
 2.1 Identification Targets
Other drugs exert their effects by interacting with a
different class of macromolecules called nucleic
acids, which consist of long chains of nucleotide
residues.
some drugs form
covalent bonds with
their targets,
in the majority of
cases, including
those in Protein target
and Nucleic Acid
 2.1 Identification Targets
• Noncovalent interactions are responsible for the affinity
between the drug and the target. The main classifications
of such noncovalent attractive forces are ionic
interactions, ion–dipole interactions, dipole–dipole
interactions, hydrogen bonding, charge– transfer
complexes, hydrophobic interactions, cation–π
interactions, halogen bonding, and van der Waals
forces.
• For example, a negatively charged moiety on the drug will
be attracted to a positively charged residue on the target,
or a phenyl ring on the drug will be attracted to the
hydrophobic side chains of amino acids such as
phenylalanine, leucine, valine, and others.
 2.1 Identification Targets

Interaction of the drug zanamivir with its enzyme target neuraminidase.

 2.1 Identification of Targets

Nucleic acids, for example, DNA, have an important role in cell

replication, and drugs that bind to DNA can disrupt this
function. This mechanism is responsible for the action of some
anticancer and anti-infective drugs
 2.2 Validation of Targets
• It has been estimated that there are only 324 drug
targets for all classes of approved drugs (266 are
human-genome derived proteins; the rest are
pathogen targets) and only 1357 unique drugs, of
which 1204 are small molecules and 166 are
biologics
• One approach to identify targets is to compare
the genetic make-up of a large number of
patients with the disease with that of a large
number of normal patients, and identify which
genes, and therefore the corresponding proteins
 2.2 Validation of Targets
• Another approach is to apply one of the several
methods of selectively eliminating the function of
a particular protein and observing the
consequence in an isolated biochemical pathway
or a whole animal.
• Alternatively, antibodies to a specific protein can
be developed that block the function of the
protein.
 2.2 Validation of Targets
• It has been estimated that the probability of
getting a compound for a novel target into
preclinical (animal) development is only 3%, but it
is 17% for an established target.
• However, the use of a well-established target can
result in “me-too” drugs (drugs that are
structurally very similar to already known drugs
and act by the same mechanism of action),
producing more drugs of the same class.
• With appropriate marketing, a company is able to benefit
economically from the “me-too” approach although society may
not realize a significant benefit.
 2.2 Validation of Targets

On the other hand, a novel target can lead to

drugs that have novel properties that can treat
diseases or subpopulations of diseases not
previously treated. While this approach is more
expensive and usually has a lower probability of
success, it is also potentially more rewarding
both for society and also for the finances of the
company that established the new mechanism
of treatment.
 2.3 Lead Search
First, however, it needs to be noted that drugs are
not generally discovered. What is more likely
discovered is known as a “lead compound” (or
lead). The lead is a prototype compound that has
a number of attractive characteristics, including
the desired biological or pharmacological activity,
but may have other undesirable characteristics,
for example, high toxicity, other biological
activities, absorption difficulties, insolubility, or
metabolism problems.
 2.3 Lead Search
A lead compound typically has most or all of the
following characteristics
– It interacts with the target in a manner consistent
with that needed to achieve the desired effect.
– It is amenable to synthetic modifications needed to
improve properties.
– It possesses, or can be modified to possess, physical
properties consistent with its ability to reach the
target after administration by a suitable route.
 2.3 Lead Search
Common sources of lead compounds are
(1) The natural ligand or substrate for the target of
interest
Dopamine is the natural ligand for the family of dopamine
receptors. Increasing dopamine concentrations is an important aim
for the treatment of Parkinson’s disease. Therefore, dopamine
was the lead compound for the discovery of rotigotine
 2.3 Lead Search
Common sources of lead compounds are
(2) Another substance already known to interact
with the target of interest.
• For example, the plant alkaloid cytisine and nicotine was known
to interact with nicotinic acetylcholine receptors. Cytisine was
the lead compound used for the Pfizer’s development of
varenicline a drug that helps patients quit smoking.
 2.3 Lead Search
Common sources of lead compounds are
(3) Random or targeted screening
• Screening refers to the exercise of conducting a biological assay on
a large collection of compounds to identify those compounds that
have the desired activity. Initially, these compounds may bind
weakly to the target and are known as hits. Hits can be considered
as predecessors to leads.
• Assays that rapidly measure binding affinities to targets of interest,
called high-throughput screens. For example, activation of
dopamine receptors, increase in the concentration of Ca2+ ions
inside the cell & measurement of changes in the intracellular Ca2+
concentration in cells (with Ca2+-sensitive dyes) that express
dopamine receptors (either naturally or by transfection) can be
used to identify ligands for these receptors.
 2.3 Lead Search
Common sources of lead compounds are
(4) Fragment-based screening
• Several screening methods using, for example, X-ray
crystallography or NMR spectrometry have been developed to
identify simple molecules (fragments) possessing typically modest
affinity for a target, with the intent of connecting two or more of
these fragments to create a useful lead compound.

(5) Computational approaches