NEW DRUG
DISCOVERY
Dr. Pravina Koteshwar
ICRI, Bangalore
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 - Process
• Target Identification
• Target validation
• Rational Drug Design
• Lead Identification
• Lead Optimization
Target Identification
• What is a drug Target?
• Types of drug targets
• Objectives of target identification
• Techniques used
Target Identification
Drug Targets
Receptors
Enzymes
Transporters
Ion channels
Genes
(95 % of available targets are proteins in nature)
Target Identification
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 %
Year 2000
Target Identification -Objectives
2. New & innovative drug development
3. To select new & clinically relevant
molecular targets
4. To enhance R&D productivity
Target Identification Techniques
Classical – Molecular biology
Cellular biology
Modern - Genomics
Proteomics
Bioinformatics
( In silico identification )
Target Identification Techniques
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
Target Identification Techniques
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
Target Identification Techniques
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.
Target Identification Techniques
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
Target Identification Techniques
Bioinformatics
Systematic acquisition, analysis and
interpretation of large amount of data
generated from biological information.
Tool box for genomics & proteomics
DRUG TARGETS
Obesity Diabetes
Leptin Insulin
Gherlin GLUT4
Xenical GLUT1
Obestatin PPAR gamma
DPP IV
Alpha amylase
Alpha glucosidase
DRUG TARGETS
Hyperlipidemia
HMG Co A reductase
LDL
VLDL degradation
Intestinal cholesterol
absorption – Lipase
Microsomal triglyceride
transfer protein
Target Validation
Objectives
Techniques of target validation
Significance
Target Validation
Objectives
• Demonstration of clinical relevance of TARGET
in a disease process (gain or loss of biological
function)
• To develop a selective & efficacious new drug
Target Validation
• 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
Target Validation Techniques
Genomics
Transgenic animals – Knock-in & Knock-out
Proteomics
RNA & Protein expression analysis
Validating a TARGET
Obesity Diabetes
Leptin Insulin
Gherlin GLUT4
Xenical GLUT1
Obestatin PPAR gamma
DPP IV
Alpha amylase
Alpha glucosidase
Rational drug design
Aim
Approaches for drug design & lead identification
• Classical
• Modern
Significance
Rational drug design
Aim
To develop a successful drug candidate by
means of lead identification & optimization
Approaches
Classical approach
Modern approach
Rational drug design
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
Classical approaches in
Rational drug design
• Synthetic derivatives
Aspirin,
Digoxin,
Pethidine
Chloroquine,
Classical approaches in
Rational drug design
• 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----)
Approaches for lead identification
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
Lead Identification
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
How is Lead Optimization
accomplished?
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
Lead Optimization
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
