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. 2. 3. 4. 5. 6. 7.

Idea or hypothesis New drug discovery Screening Preclinical studies Formulation development Clinical studies 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 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 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 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 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