Seminr on overview of drug discovery and development converted

SEMINR ON OVERVIEW OF
DRUG DISCOVERY AND
DEVELOPMENT
1
Department of Pharmacology BVVS COP BGK

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

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.
3

❖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. 4

➢ 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.
5

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

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

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.
8

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.
9

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.
10

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.
11

❖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.
12

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.
13

❖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
14

❖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.
15

16

17

❖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.
18

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
19

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

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
21

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.
22

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.
23
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.

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.
24
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.

❖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.
25

❖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
26

❖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.
27

Lead optimization requires the simultaneous
optimization of multiple parameters and is thus a
time consuming and costly step.
28

❖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.
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.
29

❖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.
30

➢ 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 draws 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.
➢ 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.
31

THANK U
32

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