Drug discovery and development-药物发现与发展

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,12/26/2011,#,Drug Discovery&Development,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,Herbal Drugs,Serendiptious discoveries,1920s, 30s,Vitamins,Vaccines,1940s,Antibiotic Era,R&D Boost due to WW2,1950s,New technology,Discovery of DNA,1960s,Breakthrough in Etiology,1970s,Rise of Biotechnology,Use of IT,1980s,Commercialization of Drug Discovery,Combinatorial Chemistry,1990s,Robotics,Automation,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,$800 M spent to bring a new drug to market.,$127 Billion spent on Pharma R&D in 2010,Share of CROs in research operations is 27%,World CRO market is 16.3 B (Indian share $500 M),Market Scenerio,:,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,$391 Million,Top CROs,(India),Contract,Research Organizations,Location,Actimus Biosciences,Hyderabad,Advinus Therapeutics,Bangalore,Aurigene Discovery technologies,Bangalore,Chembiotek,Kolkata,GVK Biosciences,Hyderabad,Jubilant Organosys,Bangalore,Ranbaxy Life Sciences,Mumbai,Reliance,Life Sciences,Mumbai,Suven Life Sciences,Hyderabad,Syngene,Bangalore,Most valuable R&D Projects,Rank,Product,Company,Phase,Pharmacological class,Todays NPV($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,4,241,6,DR Cysteamine,Undisclosed,Phase III,Lysosomal transport modulator,4,155,7,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,3,592,10,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,100.0,10,000,COMPOUNDS,250,COMPOUNDS,5 COMPOUNDS,1 FDA APPROVED DRUG,6.5 YEARS,7 YEARS,1.5 YEARS,DRUG,DISCOVERY,PRECLINICAL,CLINICAL TRIALS,FDA,REVIEW,Drug Discovery & Development-Timeline,Drug Discovery,Drugs Discovery methods:,Random Screening,Molecular Manipulation,Molecular Designing,Drug Metabolites,Serendipity,Target Selection,Cellular and Genetic Targets,Genomics,Proteomics,Bioinformatics,Lead Discovery,Synthesis and Isolation,Combinatorial Chemistry,Assay development,High-Throughput Screening,Medicinal Chemistry,Library Development,SAR Studies,In Silico Screening,Chemical,Synthesis,In Vitro Studies,Drug Affinity and Selectivity,Cell Disease Models,MOA,Lead Candidate Refinement,In Vivo Studies,Animal models of Disease States,Behavioural Studies,Functional Imaging,Ex-Vivo Studies,Clinical Trials and,Therapeutics,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Target Selection,Target selection in drug discovery is defined as the decision to focus on finding an agent with a particular biological action that is anticipated to have therapeutic utility is influenced by a complex balance of scientific, medical and strategic considerations,.,T,arget identification: to identify molecular targets that are involved in disease progression,.,T,arget validation: to prove that manipulating the molecular target can provide therapeutic benefit for patients,.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Target Selection,Biochemical Classes of Drug Targets,G-protein coupled receptors - 45%,enzymes - 28%,hormones and factors - 11%,ion channels - 5%,nuclear receptors - 2%,Techniques for Target Identification,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Cellular & Genetic Targets:,Involves the identification of the function of a potential therapeutic drug target and its role in the disease process.,For small-molecule drugs, this step in the process involves identification of the target receptors or enzymes whereas for some biologic approaches the focus is at the gene or transcription level.,Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Cellular & Genetic Targets:,Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease.,Compounds are then identified that have various interactions with the drug targets that might be helpful in treatment of a specific disease.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Genomics:,The study of genes and their function. Genomics aims to understand the structure of the genome, including the mapping genes and sequencing the DNA.,Seeks to exploit the findings from the sequencing of the human and other genomes to find new drug targets.,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.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Genomics:,Drews estimates that the number of genes implicated in disease, both those due to defects in single genes and those arising from combinations of genes, is about 1,000,Based on 5 or 10 linked proteins per gene, he proposes that the number of potential drug targets may lie between 5,000 and 10,000.,Single Nucleotide Polymorphism (SNP) libraries: are used to compare the genomes from both healthy and sick people and to identify where their genomes vary.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Proteomics:,It is the study of the proteome, the complete set of proteins produced by a species, using the technologies of large scale protein separation and identification.,It is becoming increasingly evident that the complexity of biological systems lies at the level of the proteins, and that genomics alone will not suffice to understand these systems.,It is also at the protein level that disease processes become manifest, and at which most (91%) drugs act.,Therefore, the analysis of proteins (including protein-protein, protein-nucleic acid, and protein ligand interactions) will be utmost importance to target discovery.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Proteomics:,Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems.,Target identification with proteomics is performed by comparing the protein expression levels in normal and diseased tissues.,2D PAGE is used to separate the proteins, which are subsequently identified and fully characterized with LC-MS/MS.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Bioinformatics:,Bioinformatics is a branch of molecular biology that involves extensive analysis of biological data using computers, for the purpose of enhancing biological research.,It plays a key role in various stages of the drug discovery process including,target identification,computer screening of chemical compounds and,pharmacogenomics,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Cellular & Genetic Targets,Genomics,Proteomics,Bioinformatics,Bioinformatics:,Bioinformatics methods are used to transform the raw sequence into meaningful information (eg. genes and their encoded proteins) and to compare whole genomes (disease vs. not).,Can compare the entire genome of pathogenic and non-pathogenic strains of a microbe and identify genes/proteins associated with pathogenism,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 diseased individuals at once,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Synthesis and Isolation,Combinatorial Chemistry,Assay Development,High Throughput Screening,Lead Discovery:,Identification of small molecule modulators of protein function,The process of transforming these into high-content lead series.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Synthesis and Isolation,Combinatorial Chemistry,Assay Development,High Throughput Screening,Synthesis and Isolation,:,Separation of mixture,Separation,of impurities,In vitro chemical synthesis,Biosynthetic intermediate,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Synthesis and Isolation,Combinatorial Chemistry,Assay Development,High Throughput Screening,Combinatorial Chemistry:,Rapid synthesis of or computer simulation of large no. of different but structurally related molecules,Search new leads,Optimization of target affinity & selectivity.,ADME properties,Reduce toxicity and eliminate side effects,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Synthesis and Isolation,Combinatorial Chemistry,Assay Development,High Throughput Screening,Assay Development,Used for measuring the activity of a drug.,Discriminate,between compounds.,Evaluate:,Expressed protein targets.,Enzyme/ substrate interactions.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Synthesis and Isolation,Combinatorial Chemistry,Assay Development,High Throughput Screening,High throughput screening:,Screening of drug target against selection of chemicals.,Identification of highly target specific compounds.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Synthesis and Isolation,Combinatorial Chemistry,Assay Development,High Throughput Screening,High throughput screening:,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Library Development,SAR Studies,In Silico Screening,Chemical Synthesis,Medicinal Chemistry:,Its a discipline at the intersection of synthetic organic chemistry and parmacology.,Focuses on small organic molecules (and not on biologics and inorganic compounds),Used in,Drug discovery (hits),Lead optimization (hit to lead),Process chemistry and development,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Library Development,SAR Studies,In Silico Screening,Chemical Synthesis,Library Development:,Collection of stored chemicals along with associated database.,Assists in High Throughput Screening,Helps in screening of drug target (hit),Based on organic chemistry,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Library Development,SAR Studies,In Silico Screening,Chemical Synthesis,SAR Studies:,Helps identify pharmacophore,The pharmacophore is the precise section of the molecule that is responsible for biological activity,Enables to prepare more active compound,Allow,elimination of excessive functionality,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Library Development,SAR Studies,In Silico Screening,Chemical Synthesis,SAR Studies:,Morphine,Molecule,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Library Development,SAR Studies,In Silico Screening,Chemical Synthesis,In silico screening:,Computer simulated screening of chemicals,Helps in finding structures that are most likely to bind to drug target.,Filter,enormous Chemical space,Economic,than HTS,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Library Development,SAR Studies,In Silico Screening,Chemical Synthesis,Chemical Synthesis:,Involve production of lead compound in suitable quantity and quality to allow large scale animal and eventual, extensive human clinical trials,Optimization of chemical route for bulk industrial production.,Suitable drug formulation,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Drug Affinity and Selectivity,Cell Disease Models,MOA,Lead Candidate Refinement,In Vitro Studies:,(In glass) studies using component of organism i.e. test tube experiments,Examples-,Cells derived from multicellular organisms,Subcellular components (Ribosomes, mitochondria),Cellular/ subcellular extracts (wheat germ, reticulocyte extract),Purified molecules (DNA,RNA),Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Drug Affinity and Selectivity,Cell Disease Models,MOA,Lead Candidate Refinement,In Vitro Studies:,Advantages:,Studies can be completed in short period of time.,Reduces risk in post clinical trials,permits an enormous level of simplification of the system,investigator can focus on a small number of components,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Drug Affinity and Selectivity,Cell Disease Models,MOA,Lead Candidate Refinement,Drug affinity and selectivity,Drug affinity,is,the ability of drug,to bind to its biological target (receptor, enzyme, transport system, etc.),Selectivity-,Drug should bind to specific receptor site on the cell (eg. Aspirin),Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Drug Affinity and Selectivity,Cell Disease Models,MOA,Lead Candidate Refinement,Isogenic human disease models,-,are a,family of cells that are selected or engineered to accurately model the genetics of a specific patient population, in vitro,Stem cell disease,model,s,-,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,Cell disease models,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Drug Affinity and Selectivity,Cell Disease Models,MOA,Lead Candidate Refinement,Optimizing chemical hits for clinical trial is commonly referred to as,lead optimization,The refinement in structure is necessary in order to improve,Potency,Oral Availability,Selectivity,pharmacokinetic properties,safety,(,ADME,properties,),Lead Candidate refinement,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Animal models of Disease States,Behavioural Studies,Functional Imaging,Ex-Vivo Studies,In vivo studies,Its experimentation using a whole, living organism.,Gives information about,Metabolic profile,Toxicology,Drug interaction,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Animal models of Disease States,Behavioural Studies,Functional Imaging,Ex-Vivo Studies,Animal models of disease states,Test conditions involving induced disease or injury similar to human conditions.,Must,be equivalent in mechanism of cause.,Can,predict human toxicity in 71% of the cases.,Eg. SCID mice-HIV,NOD,mice-,Diabetes,Danio rerio- Gene function,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Animal models of Disease States,Behavioural Studies,Functional Imaging,Ex-Vivo Studies,Behavioural Studies,Tools to investigate behavioural results of drugs.,Used,to observe depression and mental disorders.,However,self esteem and suicidality are hard to induce.,Example:,Despair based- Forced swimming/,T,ail suspension,Reward,based,Anxiety,Based,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Animal models of Disease States,Behavioural Studies,Functional Imaging,Ex-Vivo Studies,Functional Imaging:,Method of detecting or measuring changes in metabolism, blood flow, regional chemical composition, and absorption.,Tracers or probes used.,Modalities Used-,MRI,CT-Scan,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Animal models of Disease States,Behavioural Studies,Functional Imaging,Ex-Vivo Studies,Ex-Vivo Studies:,Experimentation on tissue in an artificial environment outside the organism with the minimum alteration of natural conditions.,Counters ethical issues.,Examples:,Measurement,of tissue properties,Realistic,models for surgery,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Phase-I,Phase-II,Phase-III,Phase-IV,Clinical trials:,Set of procedures in medical research and drug development to study the safety and efficacy of new drug.,Essential to get marketing approval from regulatory authorities.,May require upto 7 years.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Phase-I,Phase-II,Phase-III,Phase-IV,Phase 0:,Recent,designation, also known as human micro-dosing studies.,F,irst in human trials, conducted to study exploratory investigational new drug.,Designed to,to speed up the development of promising drugs.,Concerned with-,P,reliminary data on the drugs pharmacodynamics and pharmacokinetics,Efficacy of pre-clinical studies.,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Phase-I,Phase-II,Phase-III,Phase-IV,Phase I:,Clinical Pharmacologic Evaluation,First,stage of testing in human subjects.,20-50 Healthy Volunteers,Concerned With:,Human Toxicity.,Tolerated Dosage Range,Pharma-cology/dynamics,Target Selection,Lead Discovery,Medicinal Chemistry,In Vitro Studies,In Vivo Studies,Clinical Trials,Phase-I,Phase-II,Phase-III,Phase-I