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
1. Target Identification
2. Target validation
3. Rational Drug Design
4. Lead Identification
5. 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
1. New & innovative drug development
2. To select new & clinically relevant molecular targets
3. To enhance R&D productivity
Target Identification TechniquesClassical – Molecular biology
Cellular biology
Modern - Genomics
Proteomics
Bioinformatics
( In silico identification )
Target Identification Techniques
Aim of modern methodsDiscovering newer genes & proteinsIncrease the number of disease targets ten
foldQuantifying & 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
GenomicsStudy of DNA sequences / gene map of an organismHuman genome Project
e.g. Leptin gene in obesity
TechniquesGene expression Microarray
GenomicsDisease Genetics – Genes responsible for certain diseasesClinical trait data
Pharmacogenomics –Genes determining the drug response whether desired
or undesired
PharmacogeneticsGenetic 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
ProteomicsSystematic 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
Leptin
Gherlin
Xenical
Obestatin
Diabetes
Insulin
GLUT4
GLUT1
PPAR gamma
DPP IV
Alpha amylase
Alpha glucosidase
DRUG TARGETS
Hyperlipidemia
HMG Co A reductase
LDL
VLDL degradationIntestinal 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 TechniquesTarget – Ligand interactions
Classical – Cellular biologyMolecular 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
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
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 originSalicylic acid - willow bark, Digitalis - fox glove,Quinine - Cinchona bark,opium – poppy seeds
Animal originCod liver oil, Omega 3 fatty acids – fish oil, etc
Classical approaches in Rational drug design
• Synthetic derivatives
Aspirin, Digoxin, PethidineChloroquine,
Classical approaches in Rational drug design
• Chemical alteration of an existing molecule
Acetaminophen & NSAIDsDigitoxin 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, metabolismPatentability
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 interestOff-target pharmacological activities
should be minimumBetter solubility for both oral & parenteral
preparationsCYP-450: lesser drug – drug interactionMultiple 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 siteangiotensin-converting enzyme inhibitors