Drug Discovery & Design 3

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NEW DRUG DISCOVERYDr. Pravina Koteshwar ICRI, Bangalore

New Drug Discovery - OverviewIntroduction 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, Alzheimers; obesity); low efficacy (dementia, cancer); side effects (antidepressants, antipsychotics) cost of therapy; (Interleukins) costs to individual/country; (Alzheimers; spinal injury, depression) sustain industrial activity; pharmaceutical industry

employs thousands and makes a massive contribution to overseas earnings); patent expiry

Steps in New Drug Development1. 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 IdentificationDrug Targets Receptors Enzymes Transporters Ion channels Genes(95 % of available targets are proteins in nature)

Target IdentificationCurrent 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 -Objectives2. New & innovative drug development 3. To select new & clinically relevant molecular targets 4. To enhance R&D productivity

Target Identification TechniquesClassical Molecular biology Cellular biology Modern - Genomics Proteomics Bioinformatics ( In silico identification )

Target Identification TechniquesAim 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 TechniquesMolecular 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 TechniquesGenomicsStudy of DNA sequences / gene map of an organism Human genome Project e.g. Leptin gene in obesity TechniquesGene expression Microarray

GenomicsDisease 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 chipa 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 TechniquesProteomicsSystematic high throughput characterization of proteins within a biological systemAnalysis of synthesis, structure & function of proteins e.g. Leptin in obesity, beta amyloid in Alzheimers Techniques Gel electrophoresis, Mass spectrometry

Target Identification TechniquesBioinformaticsSystematic acquisition, analysis and interpretation of large amount of data generated from biological information. Tool box for genomics & proteomics

DRUG TARGETSObesity Leptin Gherlin Xenical Obestatin Diabetes Insulin GLUT4 GLUT1 PPAR gamma DPP IV Alpha amylase Alpha glucosidase

DRUG TARGETSHyperlipidemia HMG Co A reductase LDL VLDL degradationIntestinal cholesterol absorption Lipase Microsomal triglyceride transfer protein

Target ValidationObjectives Techniques of target validation Significance

Target ValidationObjectives 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 automationDruggability Ability of protein to respond to drug treatment

Target Validation TechniquesTarget Ligand interactions Classical Cellular biology Molecular biology Inhibitors, agonists, antagonists Modern Genomics Proteomics

Target Validation TechniquesGenomics Transgenic animals Knock-in & Knock-out Proteomics RNA & Protein expression analysis

Validating a TARGETObesity Leptin Gherlin Xenical Obestatin Diabetes Insulin GLUT4 GLUT1 PPAR gamma DPP IV Alpha amylase Alpha glucosidase

Rational drug designAim Approaches for drug design & lead identification Classical Modern Significance

Rational drug designAim To develop a successful drug candidate by means of lead identification & optimization Approaches Classical approach Modern approach

Rational drug designClassical approaches Natural products screening Synthetic derivatives Chemical alteration of an existing molecule

Classical approaches in Rational drug design Natural products screeningPlant 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 derivativesAspirin, Digoxin, Pethidine Chloroquine,

Classical approaches in Rational drug design Chemical alteration of an existing moleculeAcetaminophen & NSAIDs Digitoxin Mefloquine, Arteether, Penicillins, Cephalosporins

Rational drug designModern approaches Combinatorial chemistry Molecular modelling CADD, Pharmacophore Proteins recombinant technology Gene therapy

Lead IdentificationCharacterization of DRUG molecule Characterization of LEAD molecule Approaches for lead identification Rational approach in detail

Characterization of DRUG moleculeLipinskis 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: Lipinskis rule of five Pharmacokinetic: bioavailability, metabolism Patentability

Approaches for lead identification

Serendipity Random approach Rational approach (rational drug design----)

Approaches for lead identification

SerendipityPenicillin, Digitalis, Chloroquine,

Random approachSulfonamide, tetracycline, Zidovudine

Rational approach for lead identificationChemical source Empirical screening (SAR) Virtual screening (3D imaging) NMR based screening

Promising moleculesPharmacological (PD)


Lead IdentificationHitsPharmacological (PD,PK Safety) & chemical


Lead IdentificationPharmacological 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 OptimizationLeadsPharmacological (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 OptimizationMost 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 processbreast cancer (tamoxifen); Parkinsons disease (L-dopa)

Study biochem/physiological pathwayrenin/angiotensin system

Develop SAR to natural compoundbeta-adrenoceptors (propranolol), H2-receptors (cimetidine)

Design to fit known structurally identified biological siteangiotensin-converting enzyme inhibitors