New Drug Discovery

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 Target Validation Techniques Target – Ligand interactions Classical – Cellular biology Molecular biology – Inhibitors, agonists, Modern Genomics Proteomics Genomics Transgenic animals – Knock-in & Knock-out Proteomics RNA & Protein expression analysis Validating a TARGET Obesity Leptin Gherlin Xenical Obestatin

treatment

antagonists

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,

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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 • • • • • • Lead Optimization

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