drug discovery & design 3

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