NEW DRUG DISCOVERY

New Drug Discovery - Overview

Introduction – New Drug Development & Discovery
Historical perspective
Modern approach to drug discovery & design
Details of each step in DDD
Criteria for a molecule to become a drug, lead
Conclusion
Why are new drugs needed?
• unmet medical need;
new diseases (AIDS, Alzheimer’s; obesity);
low efficacy (dementia, cancer);
side effects (antidepressants, antipsychotics)
• cost of therapy; (Interleukins)
• costs to individual/country; (Alzheimer’s; spinal injury, depression)
• sustain industrial activity; pharmaceutical industry employs thousands and makes a massive
contribution to overseas earnings); patent expiry
Steps in New Drug Development
1. Idea or hypothesis
2. New drug discovery
3. Screening
4. Preclinical studies
5. Formulation development
6. Clinical studies
7. Official license / Regulations/Marketing
New Drug Discovery –
ProcessTarget Identification
8. Target validation
9. Rational Drug Design
10. Lead Identification
11. Lead Optimization

Target Identification
• What is a drug Target?
• Types of drug targets
• Objectives of target identification
• Techniques used
Drug Targets
 Receptors
 Enzymes
 Transporters
 Ion channels
 Genes

(95 % of available targets are proteins in nature)

Current therapy is based on 500 potential Drug Targets

• G-PCR --- 45 %
• Enzymes --- 28 %
 • Hormones & Factors --- 11 %
• Ion channels --- 05 %
• Nuclear Rc --- 02 %
• DNA --- 02 %
• Unknown --- 07 %
Target Identification -Objectives
1. New & innovative drug development
2. To select new & clinically relevant molecular targets
3. To enhance R&D productivity

Target Identification Techniques

Classical – Molecular biology
Cellular biology

Modern - Genomics
Proteomics
Bioinformatics
( In silico identification )
Aim of modern methods
 Discovering newer genes & proteins
 Increase the number of disease targets ten fold
 Quantifying & analyzing gene and protein expression patterns between diseased and normal
cells / individuals
Molecular Biology
New receptors, enzymes, ion channels using
Radioligands binding studies
Fluorescent technology

Cellular Biology
Functional cell culture assays - Rc expression & function, Enzyme expression & function

Genomics
Study of DNA sequences / gene map of an organism
Human genome Project

e.g. Leptin gene in obesity

Techniques
Gene expression Microarray
Genomics
Disease Genetics –
Genes responsible for certain diseases
Clinical trait data

Pharmacogenomics –
Genes determining the drug response whether desired or undesired

Pharmacogenetics
Genetic variations within individuals influencing differences in drug response
Gene microarray Assembly of particular DNA molecules on a chip—

a gene microarray.

A gene microarray is a square of glass smaller than a postage stamp, covered with millions of strands of DNA
arrayed like blades of grass.

Proteomics
Systematic high throughput characterization of proteins within a biological system

Analysis of synthesis, structure & function of proteins

e.g. Leptin in obesity, beta amyloid in Alzheimer’s

Techniques – Gel electrophoresis, Mass spectrometry

Bioinformatics

Systematic acquisition, analysis and interpretation of large amount of data generated from biological
information.

Tool box for genomics & proteomics

DRUG TARGETS
Obesity
Leptin
Gherlin
Xenical
Obestatin
Insulin
GLUT4
GLUT1
PPAR gamma
DPP IV
Alpha amylase
Alpha glucosidase
Hyperlipidemia
HMG Co A reductase
LDL
VLDL degradation
Intestinal cholesterol absorption – Lipase
Microsomal triglyceride transfer protein

Target Validation
Objectives
Techniques of target validation
Significance

Objectives

• Demonstration of clinical relevance of TARGET in a disease process (gain or loss of biological

function)
• To develop a selective & efficacious new drug

• A crucial decision making step in drug discovery

• A major bottleneck
• Less adaptable to automation

Druggability – Ability of protein to respond to drug treatment

Target Validation Techniques
Target – Ligand interactions

Classical –
Cellular biology
Molecular biology – Inhibitors, agonists, antagonists

Modern -
Genomics
Proteomics

Genomics
Transgenic animals – Knock-in & Knock-out

Proteomics
RNA & Protein expression analysis

Validating a TARGET
Obesity
Leptin
Gherlin
Xenical
Obestatin
Diabetes
Insulin
GLUT4
GLUT1
PPAR gamma
DPP IV
Alpha amylase
Alpha glucosidase

Rational drug design

Aim
Approaches for drug design & lead identification
• Classical
• Modern
Significance

Aim
To develop a successful drug candidate by means of lead identification & optimization

Approaches
Classical approach
Modern approach

Classical approaches

• Natural products screening

• Synthetic derivatives
• Chemical alteration of an existing molecule

Classical approaches in
Rational drug design
• Natural products screening
Plant origin
Salicylic acid - willow bark,
Digitalis - fox glove,
Quinine - Cinchona bark,
opium – poppy seeds

Animal origin
Cod liver oil,
Omega 3 fatty acids – fish oil, etc

• Synthetic derivatives

Aspirin,
Digoxin,
Pethidine
Chloroquine,
 • Chemical alteration of an existing molecule

Acetaminophen & NSAIDs

Digitoxin
Mefloquine,
Arteether,
Penicillins,
Cephalosporins

Rational drug design

Modern approaches

• Combinatorial chemistry
• Molecular modelling –CADD, Pharmacophore
• Proteins – recombinant technology
• Gene therapy
Lead Identification
Characterization of DRUG molecule
Characterization of LEAD molecule
Approaches for lead identification
Rational approach in detail

Characterization of DRUG molecule

Lipinski’s “rule of five”,

An excellent working hypothesis for predicting drug like properties in new compounds (1990s).
• Molecular Wt. 500 Da
• Solubility – H bonds
• Lipophilicity (log P)
• Aqueous solubility
• Bioavailability
Characterization of LEAD molecule
 Pharmacodynamic: efficacy, selectivity, potency
 Physicochemical: Lipinski’s “rule of five”
 Pharmacokinetic: bioavailability, metabolism
 Patentability

Approaches for lead identification

 Serendipity
 Random approach
 Rational approach (rational drug design----)

 Serendipity
Penicillin, Digitalis, Chloroquine,

 Random approach
Sulfonamide, tetracycline, Zidovudine
Rational approach for lead identification
Chemical source
– Empirical screening (SAR)
– Virtual screening (3D imaging)
– NMR based screening

Promising molecules
Pharmacological(PD)

Hits

Lead Identification
Hits

Pharmacological
(PD,PK Safety)
& chemical

Leads

Pharmacological basis
 Pharmacodynamics
 Pharmacokinetics
 Toxicology
 Physicochemical properties

Lead Optimization
• Key decision making step
• Tightest bottleneck
• Contributes to success of drug development
• Slow, time consuming
• High Cost
• Extra carefulness
Lead Optimization
Leads

Pharmacological
(PK, Safety, PD)
& chemical

Candidate drug

How is Lead Optimization accomplished?

Multistep modification procedure – optimization
of pharmacological properties
• PK
• Toxicity
• PD
• Physicochemical
Chemical modification of Pharmacophore & non pharmacophore components
• structure
• synthesis
• purity
• isomers
• pKa
• stability
• solubility
• salts
Lead Optimization
 High selectivity to target of interest
 Off-target pharmacological activities should be minimum
 Better solubility for both oral & parenteral preparations
 CYP-450: lesser drug – drug interaction
 Multiple routes of excretion

Most experienced medicinal chemists would prefer to start in a structural series that has inherently good ADME
and safety properties, albeit with poor potency on the target receptor, and then set about improving the potency on
the target, rather than working in the other direction.

Department of Basic Chemistry,

Merck Research Laboratories

Rational Approaches to drug discovery

• Study disease process

breast cancer (tamoxifen); Parkinson’s disease (L-dopa)
• Study biochem/physiological pathway
renin/angiotensin system
• Develop SAR to natural compound
beta-adrenoceptors (propranolol), H2-receptors (cimetidine)
• Design to fit known structurally identified biological site
angiotensin-converting enzyme inhibitors