introduction of the drug discovery process

1. DRUG DISCOVERY AND DEVELOPMENT
OVERVIEW
By : Shubham teli.
Mpharm – 2nd sem (pharmacology)
HSK college of pharmacy bagalkot

2. •Drug Discovery
• Drug discovery is the process through which potential new medicines are identified.
.

3. THE
METHODS
INVOLVED IN
DRUG
DISCOVERY
Target
Identification.
Target
validation.
Lead
identification.
Lead
optimization.
Purpose of Drug
Discovery
Drug discovery initiates
because there is a disease
or clinical condition
without suitable medical
products available.
Rare diseases or orphan
disease.

4. • Target Identification
• Target : A Target is a broad term which can be applied to range of biological entities which
may include for example Proteins, genes, Nucleic acid ,receptor, hormones etc…..
• The target identification is the process to identifying the direct molecular target. For
example protein or nucleic acid of small molecule. In clinical pharmacology target
identification is aimed at finding the efficacy target of a drug /pharmaceutical or other
xenobiotic.
• There is a need of find a protein (e.g. receptor) or gene associated with a disease with
which a potential drug interacts –the so-called targets.
• The drug discovery process starts with the identification of a molecular target and the
next is the target validation. During target validation, its association with a specific disease
and its ability to regulate biological processes is tested in the body.

5. • The target validation confirms that interactions with the target produce the
desired change in the behaviour of diseased cells.
• It is critical step in drug discovery process. Identification of new drug targets,
target validation, biochemical assay development followed by LEAD
identification provides very important input in the development of new
potential drug candidate.
• Target identification and mechanism of action studies play an important role
in small molecule discovery.

6. Target Identification
Biochemical classes of Drug targets
• G-protein coupled receptors – 45%
• Enzymes – 28%
• Harmone and factors – 11%
• Ion channels – 5%
• Nuclear receptors – 2%

7. Techniques for Target selection
The techniques applied for the target selection
• Cellular and Genetics
• Genomics
• Proteomics
• Bioinformatics

8. Cellular and Genetic Targets
• Drugs usually act on either cellular or genetic chemicals in the
body known as targets, which are believed to be associated with
disease.
• Identification of the function of a potential drug target.
• Its role in the disease process.
• Identification of the target receptors or enzymes for small molecule
drugs.
• Identification of drug target interactions.
• Focus at gene or transcription level.

9. Genomics
• Aims to understand the structure of the genome, including the
mapping genes and sequencing the DNA.
• Exploits the genome sequences of organisms and their variations in
diseases to find new drug targets.
• Introduce the concept of personalized medicine by designing drug
according to patient’s genome sequence.
• Monitor differential expressions of genes in diseased states like
SNPs and use them as biomarkers for disease diagnosis.
• Study of a drug’s mechanism of action by gene expression profiling
in microarrays.

10. Proteomics
• Proteomics is a study of the proteome, the complete set of
proteins produced by a species, using the technologies of
large scale protein separation and identification.
• Focus on analysis of proteins including protein-protein ,
protein-nucleic acid, and protein ligand interactions
• Target identification is performed by comparing the
protein expression levels in normal and diseased tissues.
• 2D PAGE is used to separate the proteins, which are
subsequently identified and fully characterized with LC-
MS/MS.

11. Bio informatics
• A branch of molecular biology that involves extensive analysis of
biological data using computers, for the purpose of enhancing biological
research.
• Methods to sequence genes and their encoded proteins and to compare
whole genomes.
• Can compare the entire genome of pathogenic and non –pathogenic
strains of a microbe.
• Identify genes or proteins associated with pathogenicity.
• Can evaluate and compare up to 20000 genes of healthy and diseased
individuals at once using microarrays.

12. •Target Validation
 Target validation is the process by which the predicted molecular
target – for example protein or nucleic acid of a small molecule is verified.
 Target validation can include knockdown or overexpression of the presumed
target.

13. siRNA
• Small (or short) interfering RNA (siRNA) is the commonly used for RNA
interference (RNAi) tool for inducing short-term silencing of protein coding
genes.
• It is a double stranded RNA molecule which interferes with the expression of
specific genes by degrading mRNA after transcription & preventing
translation.
• siRNA is double stranded RNA(dsRNA). It consist of two RNA strands, an
antisense (or guide) strand and a sense (or passenger) strand, which form a
duplex
• 20-24 bp length.

14. MECHANISM
Long dsRNA is cleaved by an endo-
ribonuclease called Dicer to form
short interfering RNA or siRNA.
siRNA enters the cell and binds to
Argonaute protein to form RISC.
siRNA is then un winded to form
single stranded siRNA.
siRna and RISC complex find their
complementary mRNA

15. ANTISENSE OLIGONUCLEOTIDE
 Antisense technology prevent the synthesis of specific protein.
 AS - ONS;15-20 nucleotides which are complementary to their target mRNA.
When these AS-ON combined with target mRNA, a DNA/RNA hybrid form
which degraded by the enzyme RNase H.
RNase H is a non specific endonuclease which catalyse cleavage of RNA.
RNase H has ribonuclease activity cleaves the 3’-O-P bond of RNA in a
DNA/RNA duplex.

18. Lead identification
Lead compound
 Chemical compound that has pharmacological or biological activity likely to
be therapeutically useful.
 Also called developmental candidates, because the discovery and selection of
lead compounds occurs prior to preclinical and clinical development of the
candidate.

19. Criteria for leads
• Pharmacodynamic properties - efficacy, potency, selectivity
• Physiochemical properties - water solubility, chemical stability
• Pharmacokinetic properties - metabolic stability and toxological aspects.
• Chemical optimization potential - ease of chemical synthesis and
derivatization.
• Patentability

20. Lead Identification
•Organic compounds are identified
which interact with the target protein
and modulate its activity by using
random (screening) or rational (design)
approaches.

21. High-throughput Screening
•Natural product and synthetic
compound libraries with millions of
compounds are screened using a test
assay.
•In theory generating the entire
‘chemical space’ for drug molecules and
testing them would be an elegant
approach to drug discover

22. Structure Based Drug Design
•Three dimensional structures of compounds
from virtual or physically existing libraries are
docked into binding sites of target proteins with
known or predicted structure.
•Scoring functions evaluate the steric and
electrostatic complementarity between
compounds and the target protein. The highest
ranked compounds are then suggested for
biological testing.

23. Methods of lead Identification
I)Random screening : All compounds including synthetic
chemicals, natural products of plant, marine and microbial
origin from a given series are tested. Inspite of budgetary
and manpower overuse, this method may be used to
discover drugs or leads that have unexpected activities.
Antibiotics like, streptomycin and tetracyclines were found
out by this method.

24. •ii) Non random screening: It is a modified form of
random screening which was developed because of
budgetary and manpower restrictions. In this method,
only such compounds having similar structural
skeletons with that of lead, are tested.

25. iii) Drug metabolism studies :
• Structural modifications are done in drug
molecule by the enzymes to increase
•its polarity. The discovery of sulfanil amide is
reported through the metabolic studies of
prontosil.

26. •iv) Clinical observations:
• Many times the drug possesses more than one
pharmacological activities. The main activity is
called as therapeutic effect while rest of the
actions is known as side effects of the drug.
•Such drug may be used as lead compound for
structural modifications to improve the potency of
secondary effects.

27. Rational approaches to lead discovery
• The knowledge about the receptors and their mode of interaction with
drug molecules plays an important role in drug design.
• This knowledge may be used to develop conformationally bioactive
skeletons having exact three-dimensional complementarity to a
receptor.
• Greater potency, higher selectivity and less adverse effects are expected
by reducing the flexibility of the drug structure.
• This approach is of greater importance in identification of lead nucleus.
• It involves the use of signs and symptoms of the disease.

28. • Lead Optimization
• Molecules are chemically modified and subsequently characterized in
order to obtain compounds with suitable properties to become a drug.
• Leads are characterized with respect to pharmacodynamic properties such
as efficacy and potency in vitro and in vivo, physiochemical properties,
pharmacokinetic properties, and toxicological aspects.
• Once compounds with desirable in vitro profiles have been identified, these
are characterized using in vivo models

29. •Characterizing Leads
Potency refers to the amount of drug required for its specific
effect to occur
Efficacy measures the maximum strength of the effect itself, at
saturating drug concentrations.
Pharmacokinetics -“what the body does to the drug.”
Pharmacodynamics –
• determining the biochemical and physiological effects of drugs
• the mechanism of drug action and
• the relationship between drug concentration and effect.

30. •Lead optimization requires the simultaneous
optimization of multiple parameters and is
thus a time consuming and costly step.

31. Methods of Lead Optimization in Analog Design
1. Identification of the active part (Pharmacophore).
2. Functional group optimization.
3. Structure activity relationship studies.
4. Bio isosteric replacement.
5. Design of rigid analogs.
6. Homologation of alkyl chains or alteration of chain branching, design of
aromatic ring position isomers, alteration of ring size, and substitution of an
aromatic ring for a saturated one or the converse.

32. • 7. Alteration of stereochemistry, or design of geometric isomers or
stereoisomers.
• 8. Design of fragments of the lead molecule that contain the
pharmacophoric group (bond disconnection).
• 9. Alteration of interatomic distances within the pharmacophoric group or
in other parts of the molecule.

33. • Economics of drug discovery
• Research based pharmaceutical companies, on average, spend about
20% of their sales for R&D. This percentage is significantly higher
than in virtually any other industry, including electronics, aerospace,
automobiles and computers.
• Since 1980, U.S pharmaceutical companies have practically doubled
spending on R&D every five years.
• Despite these enormous expenditures and efforts of pharmaceutical
companies, there has been a steady decline in the number of drugs
introduced each year into human therapy, from 70-100 in the 1960s,
60-70 in the 1970s, to about 50 in the 1980s and below 40 in the 1990s.

34. • In 1996, the term “innovation deficit” was introduced by Jurgen drews,
president of international research at Hoffman-la-Roche. “innovation deficit”
defines the gap between the number of new chemical entities (NCEs)
required to be launched in order to accomplish an annual 10% revenue
increase and the actual number of NCEs introduced in the market by the
top ten pharmaceutical companies. While drews predicted a deficit of 1.3
NCEs per company for 1999, a world leading management consulting firm
recently published a real lack of 1.5 NCEs in 2000 and expected this trend to
continue, resulting in a deficit of 2.3 NCEs by 2005.

35. • A new drug today requires an average investment of $880 million and
15 years of development, including the cost and time to discover
potential biological targets. About 75% of this cost (~$660 million) is
attributable to failure along the pharmaceutical value chain. For
example, 90% of all drug development candidates fail to make it to
the market. Out of the ~15years in development time of a successful
compound, about 6 years are devoted to the drug discovery and the
preclinical phase, 6.7 years to clinical trials and 2.2 years to the
approval phase.