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Drug discovery and development

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Brief account of drug discovery by molecular designing approach and drug development.

Brief account of drug discovery by molecular designing approach and drug development.

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    Drug discovery and development Drug discovery and development Presentation Transcript

    • Introduction• In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery.• But now we know diseases are controlled at molecular and physiological level.• Also shape of an molecule at atomic level is well understood.• Information of Human Genome
    • History of Drug Discovery : Pre 1919 1970s 1980s • Herbal Drugs • Rise of Biotechnology • Commercialization of • Serendiptious discoveries • Use of IT Drug Discovery • Combinatorial Chemistry 1920s, 30s 1960s 1990s • Vitamins • Breakthrough in Etiology • Robotics • Vaccines • Automation 1940s 1950s • Antibiotic Era • New technology, • R&D Boost due to WW2 • Discovery of DNA
    • Registration:• The Ministry of health & Family Welfare and the Ministry of Chemicals & Fertilizers have major role in regulation of IPM.• NDA must be submitted to DCGI• Phase III study reported to CDL, Kolkata• Package inserted approved by DCI• Marketing approval from FDA
    • Market Scenerio:• ~$800 M spent to bring a new drug to market.• $127 Billion spent on Pharma R&D in R&D Share 2010 18.8• Share of CROs in research operations is 27%• World CRO market is 16.3 B (Indian share $500 M)
    • Top CROs (By Revenue) Contract Research Organizations Revenue Quintiles $2.5 Billion Pharmaceutical Product Development $1.8 Billion Covance $1.4 Billion Charles River Laboratories $1.2 Billion Parexel $930 Million Icon $887 Million Kendle $590 Million Pharmanet $470 Million PRA International $410 Million 4G Pharmacovigilance $391 Million
    • Top CROs (India) Contract Research Organizations Location Actimus Biosciences Hyderabad Advinus Therapeutics Bangalore Aurigene Discovery technologies Bangalore Chembiotek Kolkata GVK Biosciences Hyderabad Jubilant Organosys Bangalore Ranbaxy Life Sciences Mumbai Reliance Life Sciences Mumbai Suven Life Sciences Hyderabad Syngene Bangalore
    • Most valuable R&D Projects TodaysRank Product Company Phase Pharmacological class NPV($mn) 1 Degludec Novo Nordisk Phase III Insulin 5,807 2 Tofacitinib Pfizer Phase III JAK-3 inhibitor 4,953 3 BG-12 Biogen Idec Phase III Fumarate 4,666 4 Incivek J&J Phase IV Hep C protease inhibitor 4,332 5 Relovair Theravance Phase III Corticosteroid 4,241 Lysosomal transport 6 DR Cysteamine Undisclosed Phase III 4,155 modulator 7 AMR 101 Undisclosed Phase III Omega-3 fatty acid 4,052 8 Eliquis Bristol Myers Squibb Phase IV Factor Xa inhibitor 3,836 9 Eliquis Pfizer Phase IV Factor Xa inhibitor 3,59210 Bexssero Novartis Phase IV Meningococcal B vaccine 3,250
    • Top Companies by R&D Expense: Sr. No. Company R & D spend($bn),2010 1 Novartis 7.9 2 Merck & Co 8.1 3 Roche 7.8 4 GlaxoSmithKline 5.7 5 Sanofi 5.8 6 Pfizer 9.1 7 Johnson & Johnson 4.5 8 Eli Lilly 4.7 9 AstraZeneca 4.2 10 Takeda 3.4 11 Bayer 2.3 12 Bristol-Myers Squibb 3.3 13 Boehringer Ingelheim 3.1 14 Amgen 2.8 15 Novo Nordisk 1.7
    • Drug Development Cost Break-up R&D Function % Discovery/Basic Research Synthesis & Extraction 10.0 Biological Screening & testing 14.2 Preclinical Testing Toxicology & Safety testing 4.5 Pharmaceutical Dosage Formulation 7.3 Clinical Trials Phase I, II, III 29.1 Phase IV 11.7 Manufacturing & QC 8.3 IND & NDA 4.1 Bioavailability 1.8 Others 9.0 Total 100.0
    • DRUG Drug Discovery & DISCOVERY Development-Timeline PRECLINICAL CLINICAL TRIALS FDA 10,000 250 REVIEW 1 FDACOMPOUNDS COMPOUNDS 5 COMPOUNDS APPROVED DRUG ~6.5 YEARS ~7 YEARS ~1.5 YEARS
    • Drug Discovery• Drugs Discovery methods: – Random Screening – Molecular Manipulation – Molecular Designing – Drug Metabolites – Serendipity
    • Target Lead Medicinal In Vitro In Vivo Clinical Selection Discovery Chemistry Studies Studies Trials and Therapeutics• Cellular and • Synthesis and • Library • Drug Affinity • Animal Genetic Isolation Development and models of Targets Selectivity Disease States• Genomics • Combinatorial • SAR Studies • Cell Disease • Behavioural Chemistry Models Studies• Proteomics • Assay • In Silico • MOA • Functional development Screening Imaging• Bioinformatics • High- • Chemical • Lead • Ex-Vivo Throughput Synthesis Candidate Studies Screening Refinement
    • Target Selection • Target selection in drug discovery is defined as the decision to focus on finding an agent with a particular Cellular &Genetic Targets biological action that is anticipated to have therapeutic utility — is influenced by a complex balance of scientific, medical and strategic considerations. Genomics • Target identification: to identify molecular targets that are involved in disease progression. Proteomics • Target validation: to prove that manipulating the molecular target can provide therapeutic benefit for patients.Bioinformatics Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Target Selection Biochemical Classes of Drug Targets  G-protein coupled receptors - 45% Cellular &Genetic Targets  enzymes - 28%  hormones and factors - 11% Genomics  ion channels - 5%  nuclear receptors - 2% Proteomics Techniques for Target IdentificationBioinformatics Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Cellular & Genetic Targets: Involves the identification of the function of a potential therapeutic drug target and its role in the disease process. Cellular &Genetic Targets For small-molecule drugs, this step in the process involves identification of the target receptors or enzymes whereas for some biologic Genomics approaches the focus is at the gene or transcription level. Proteomics Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease.Bioinformatics Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Cellular & Genetic Targets: Scientists use a variety of techniques to identify and Cellular & isolate individual targets to learn more about theirGenetic Targets functions and how they influence disease. Genomics Compounds are then identified that have various Proteomics interactions with the drug targets that might be helpful in treatment of a specific disease.Bioinformatics Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Genomics: The study of genes and their function. Genomics aims to understand the structure of the genome, including the mapping Cellular & genes and sequencing the DNA.Genetic Targets Seeks to exploit the findings from the sequencing of the human Genomics and other genomes to find new drug targets. Proteomics Human Genome consists of a sequence of around 3 billion nucleotides (the A C G T bases) which in turn probably encode 35,000 – 50,000 genes.Bioinformatics Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Genomics: Drew’s estimates that the number of genes implicated in disease, both those due to defects in single genes and those Cellular & arising from combinations of genes, is about 1,000Genetic Targets Based on 5 or 10 linked proteins per gene, he proposes that the Genomics number of potential drug targets may lie between 5,000 and 10,000. Proteomics Single Nucleotide Polymorphism (SNP) libraries: are used to compare the genomes from both healthy and sick people and toBioinformatics identify where their genomes vary. Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Proteomics: It is the study of the proteome, the complete set of proteins produced by a species, using the technologies of large – scale protein Cellular & separation and identification.Genetic Targets It is becoming increasingly evident that the complexity of biological systems lies at the level of the proteins, and that genomics alone will Genomics not suffice to understand these systems. It is also at the protein level that disease processes become manifest, Proteomics and at which most (91%) drugs act. Therefore, the analysis of proteins (including protein-protein, protein-Bioinformatics nucleic acid, and protein ligand interactions) will be utmost importance to target discovery. Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Proteomics: Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems. Cellular &Genetic Targets Target identification with proteomics is performed by comparing the protein expression levels in normal and Genomics diseased tissues. Proteomics 2D PAGE is used to separate the proteins, which are subsequently identified and fully characterized with LC- MS/MS.Bioinformatics Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Bioinformatics: Bioinformatics is a branch of molecular biology that involves extensive analysis of biological data using computers, for the purpose of enhancing biological research. Cellular &Genetic Targets It plays a key role in various stages of the drug discovery process including Genomics  target identification  computer screening of chemical compounds and Proteomics  pharmacogenomicsBioinformatics Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Bioinformatics: Bioinformatics methods are used to transform the raw sequence into meaningful information (eg. genes and their encoded Cellular & proteins) and to compare whole genomes (disease vs. not).Genetic Targets Can compare the entire genome of pathogenic and non- Genomics pathogenic strains of a microbe and identify genes/proteins associated with pathogenism Proteomics Using gene expression micro arrays and gene chip technologies, a single device can be used to evaluate and compare the expression of up to 20000 genes of healthy and diseasedBioinformatics individuals at once Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Lead Discovery: • Identification of small molecule modulators ofSynthesis and Isolation protein functionCombinatorial • The process of transforming these into high- Chemistry content lead series. AssayDevelopment High Throughput Screening Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Synthesis and Isolation: • Separation of mixtureSynthesis and Isolation • Separation of impuritiesCombinatorial • In vitro chemical synthesis Chemistry • Biosynthetic intermediate AssayDevelopment High Throughput Screening Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Combinatorial Chemistry: Rapid synthesis of or computer simulation ofSynthesis and Isolation large no. of different but structurally related moleculesCombinatorial Chemistry • Search new leads Assay • Optimization of target affinity & selectivity.Development • ADME properties High Throughput • Reduce toxicity and eliminate side effects Screening Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Assay Development • Used for measuring the activity of a drug.Synthesis and Isolation • Discriminate between compounds.Combinatorial • Evaluate: Chemistry • Expressed protein targets. AssayDevelopment • Enzyme/ substrate interactions. High Throughput Screening Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • High throughput screening: • Screening of drug target against selection ofSynthesis and Isolation chemicals.Combinatorial • Identification of highly target specific Chemistry compounds. AssayDevelopment High Throughput Screening Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • High throughput screening:Synthesis and IsolationCombinatorial Chemistry AssayDevelopment High Throughput Screening Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Medicinal Chemistry: • It’s a discipline at the intersection of synthetic Library organic chemistry and parmacology.Development • Focuses on small organic molecules (and notSAR Studies on biologics and inorganic compounds) • Used in In Silico Screening • Drug discovery (hits) • Lead optimization (hit to lead) Chemical Synthesis • Process chemistry and development Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Library Development: • Collection of stored chemicals along with LibraryDevelopment associated database. • Assists in High Throughput Screening SAR Studies • Helps in screening of drug target (hit) In Silico Screening • Based on organic chemistry Chemical Synthesis Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • SAR Studies: • Helps identify pharmacophore LibraryDevelopment • The pharmacophore is the precise section of the molecule that is responsible for biological SAR Studies activity In Silico • Enables to prepare more active compound Screening • Allow elimination of excessive functionality Chemical Synthesis Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • SAR Studies: LibraryDevelopment SAR Studies In Silico Screening Chemical Morphine Molecule Synthesis Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • In silico screening: • Computer simulated screening of chemicals LibraryDevelopment • Helps in finding structures that are most likely to bind to drug target. SAR Studies • Filter enormous Chemical space In Silico Screening • Economic than HTS Chemical Synthesis Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Chemical Synthesis: • Involve production of lead compound in LibraryDevelopment suitable quantity and quality to allow large scale animal and eventual, extensive human SAR Studies clinical trials In Silico • Optimization of chemical route for bulk Screening industrial production. Chemical Synthesis • Suitable drug formulation Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • In Vitro Studies: • (In glass) studies using component of organism i.e. test tube Drug Affinity experimentsand Selectivity • Examples- Cell Disease • Cells derived from multicellular organisms Models • Subcellular components (Ribosomes, mitochondria) • Cellular/ subcellular extracts (wheat germ, reticulocyte MOA extract) • Purified molecules (DNA,RNA)Lead Candidate Refinement Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • In Vitro Studies: Advantages: Drug Affinity • Studies can be completed in short period of time.and Selectivity • Reduces risk in post clinical trials Cell Disease • permits an enormous level of simplification of the system Models • investigator can focus on a small number of components MOALead Candidate Refinement Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Drug affinity and selectivity • Drug affinity is the ability of drug to bind to its biological Drug Affinity target (receptor, enzyme, transport system, etc.)and Selectivity Cell Disease • Selectivity- Drug should bind to specific receptor site on the Models cell (eg. Aspirin) MOALead Candidate Refinement Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Cell disease models • Isogenic human disease models- are a family of cells that are Drug Affinity selected or engineered to accurately model the genetics of a specificand Selectivity patient population, in vitro Cell Disease Models • Stem cell disease models-Adult or embryonic stem cells carrying or induced to carry defective genes can be investigated in vitro to understand latent molecular mechanisms and disease characteristics MOALead Candidate Refinement Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Lead Candidate refinement • Optimizing chemical hits for clinical trial is commonly referred Drug Affinity to as lead optimizationand Selectivity • The refinement in structure is necessary in order to improve Cell Disease • Potency Models • Oral Availability • Selectivity MOA • pharmacokinetic propertiesLead Candidate • safety (ADME properties) Refinement Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • In vivo studies • Its experimentation using a whole, livingAnimal models of Disease States organism. • Gives information about, Behavioural Studies • Metabolic profile Functional Imaging • Toxicology • Drug interactionEx-Vivo Studies Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Animal models of disease states • Test conditions involving induced disease orAnimal models of injury similar to human conditions. Disease States • Must be equivalent in mechanism of cause. Behavioural Studies • Can predict human toxicity in 71% of the cases. Functional Imaging • Eg. SCID mice-HIV NOD mice- DiabetesEx-Vivo Studies Danio rerio- Gene function Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Behavioural Studies • Tools to investigate behavioural results of drugs.Animal models of Disease States • Used to observe depression and mental disorders. • However self esteem and suicidality are hard to induce. Behavioural Studies • Example: • Despair based- Forced swimming/ Tail suspension Functional Imaging • Reward based • Anxiety BasedEx-Vivo Studies Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Functional Imaging: • Method of detecting or measuring changes inAnimal models of Disease States metabolism, blood flow, regional chemical composition, and absorption. Behavioural Studies • Tracers or probes used. Functional • Modalities Used- Imaging • MRIEx-Vivo Studies • CT-Scan Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Ex-Vivo Studies: • Experimentation on tissue in an artificialAnimal models of Disease States environment outside the organism with the minimum alteration of natural conditions. Behavioural Studies • Counters ethical issues. Functional • Examples: Imaging • Measurement of tissue propertiesEx-Vivo Studies • Realistic models for surgery Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Clinical trials: • Set of procedures in medical research andPhase-I drug development to study the safety and efficacy of new drug.Phase-II • Essential to get marketing approval fromPhase-III regulatory authorities. • May require upto 7 years.Phase-IV Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Phase 0: • Recent designation, also known as human micro-dosing studies.Phase-I • First in human trials, conducted to study exploratory investigational new drug.Phase-II • Designed to to speed up the development of promising drugs. • Concerned with-Phase-III • Preliminary data on the drug’s pharmacodynamics and pharmacokineticsPhase-IV • Efficacy of pre-clinical studies. Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Phase I: • Clinical Pharmacologic EvaluationPhase-I • First stage of testing in human subjects. • 20-50 Healthy VolunteersPhase-II • Concerned With:Phase-III – Human Toxicity. – Tolerated Dosage RangePhase-IV – Pharma-cology/dynamics Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Phase I: Types of Phase-I TrialsPhase-I • SAD (Single Ascending Dose) • MAD (Multiple Ascending Dose)Phase-II • Food effectPhase-IIIPhase-IV Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Phase II: • Controlled Clinical Evaluation.Phase-I • 50-300 Patients • Controlled Single Blind TechniquePhase-II • Concerned With: – SafetyPhase-III – Efficacy – Drug ToxicityPhase-IV – Drug Interaction Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Phase III: • Extended Clinical Trials.Phase-I • Most expensive & time consuming. • 250-1000 Patients.Phase-II • Controlled Double Blind Technique. • Concerned With:Phase-III – Safety, Efficacy – Comparison with other DrugsPhase-IV – Package Insert Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • Phase IV: • Post Marketing Surveillance.Phase-I • Designed to detect any rare or long-term adverse effects.Phase-II • Adverse Drug Reaction Monitoring. • Pharmacovigilance.Phase-IIIPhase-IV Target Selection Lead Medicinal In Vitro In Vivo Clinical Discovery Chemistry Studies Studies Trials
    • DRUG Drug Discovery & DISCOVERY Development-Timeline PRECLINICAL CLINICAL TRIALS FDA 10,000 250 REVIEW 1 FDACOMPOUNDS COMPOUNDS 5 COMPOUNDS APPROVED DRUG ~6.5 YEARS ~7 YEARS ~1.5 YEARS
    • Gene Therapy• Technique for correcting defective genes.• It is the process of inserting genes into cells to treat diseases.• Gene therapy is used to correct a deficient phenotype.
    • Gene Therapy-ApproachesGermline Gene Therapy Sperm or eggs, are modified by the introduction of functional genes, which are integrated into their genomes. Change would be heritable and would be passed on to later generations.Somatic Gene Therapy The therapeutic genes are transferredInto the somatic cells of a patient. Change will not be inherited by thepatients offspring or later generations.
    • Gene Therapy- TypesEx Vivo Gene Therapy Transfer of therapeutic genes in cultured cells which are then reintroduced into patient.Eg: Therapy for ADA DeficiencyIn Vivo Gene Therapy The direct delivery of genes into the cells of a particular tissue is referred to as in vivo gene therapy.Eg: Therapy for Cystic fibrosis
    • Gene Therapy- Vectors• Viruses Retroviruses Adenoviruses Adeno-associated viruses Herpes Simplex viruses• Pure DNA Constructs• Lipoplexes• DNA Molecular Conjugates• Human Artificial Chromosome
    • Gene Therapy- Limitations• Short lived nature of gene therapy• Immune response• Problems with viral vectors• Multigene disorders
    • Recent Developments• Nanotechnology + gene therapy yielded treatment to torpedo cancer• Results of worlds first gene therapy for inherited blindness show sight improvement• New Method of Gene Therapy Alters Immune Cells for Treatment of Advanced Melanoma• Dual Gene Therapy Suppresses Lung Cancer in Preclinical Test
    • Orphan Drugs:• An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease.• National Organization for Rare Disorders• European Organization for Rare Diseases
    • Advantages:• Tax incentives.• Enhanced patent protection and marketing rights.• Clinical research financial subsidization.• Rise in research and developmen.• Crown Corporation.
    • Orphan Drugs Act:• 4th January 1983• 6000 Orphan Diseases• Unprofitable Drug Development• Affecting < 2,00,000 Persons• Orphan Drug Status to 1,090 Drugs• 1985 Amendment- Marketing Tourette Syndrome An Orphan Disease Exclusivity
    • FDA Orphan Drug Approvals: % Share 2 Big Pharma 19 43 Small Biopharma17 Established 19 Biopharma Small & Medium Pharma
    • Rare Diseases & Orphan Drugs:Sr. Disease Cause Orphan Drug1. Gaucher’s Disease Glucocerbrosidase Enzyme Miglustat2. Fabry’s Disease Galactosidase Enyme Galsidase β3. Mucopolysaccharidosis Lysosomal Enzyme Laronidase4. Tourette’s Syndrome Motor Tics Lamotrizine5. Crohn’s Syndrome Unknown Infliximab6. Wilson Disease Copper Deposition Trientine7. SCID Adenosine Deaminase Enzyme Pegadimase