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Drug discovery
The document provides an overview of the drug discovery and development process. It discusses the various stages involved, including target selection using genomics, proteomics and bioinformatics; lead discovery through synthesis, isolation and high-throughput screening; medicinal chemistry such as structure-activity relationships studies; in vitro and preclinical in vivo testing in animal models; and clinical trials in humans. The timeline for this process can span over 10-15 years from drug target identification to regulatory approval. Key techniques and approaches at each stage are also summarized.
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Drug discovery
- 3. INTRODUCTION • In thepast 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.
- 4. HISTORY OF DRUGDISCOVERY 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
- 5. TOP COMPANIES BYR&D EXPENSE Sr. No. Company R & D spend($bn) 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
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- 7. In broader sensedrug discovery and development can be defined • “A process that starts with the identification of disease and therapeutic target of interest and include methodology, assay development ,lead identification and characterization in vitro ,formulation and animal pharmacological studies ,pharmacokinetics and safety studies in animals and clinical studies in the human .”Different stages include Basic research Feasibility studies Programme Non-Clinical development Clinical Development
- 8. 10,000 COMPOUNDS 250 COMPOUNDS 5 COMPOUNDS 1FDA APPROVED DRUG ~6.5 YEARS ~7 YEARS ~1.5 YEARS DRUG DISCOVERY PRECLINICAL CLINICAL TRIALS FDA REVIEW Drug Discovery & Development-Timeline
- 9. 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 Preclinical studies • Animal models of Disease States • Behavioural Studies • Functional Imaging • Ex-Vivo Studies Clinical Trials and Therapeutics
- 11. DRUG DISCOVERY • Itis phase during which the candidates or target of interest are selected on the basis of their pharmacological bases • Drugs Discovery methods: – Random Screening – Molecular Designing – Drug Metabolites – Serendipity
- 12. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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 • Target identification: to identify molecular targets that are involved in disease progression. • Target validation: to prove that manipulating the molecular target can provide therapeutic benefit for patients.
- 13. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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
- 14. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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 •Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease.
- 15. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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. •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.
- 16. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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 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.
- 17. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Cellular & Genetic Targets Genomics Proteomics Bioinformatics Continued…. •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.
- 18. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Cellular & Genetic Targets Genomics Proteomics Bioinformatics Bioinformatics Bioinformatics is a branch of molecular biology that involves extensive analysisof 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
- 19. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Cellular & Genetic Targets Genomics Proteomics Bioinformatics Continued… •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
- 20. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening LEAD DISCOVERY • A lead compound is an organic molecule that act as a prototype drug around which further optimization is centered and focused” • Identification of small molecule modulators of protein function • The process of transforming these into high-content lead series.
- 21. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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
- 22. Approaches For LeadDiscovery Serendipity: • It is to follow when chance is very less. It has been the historically the most successful way of discovering the drugs. E.g discovery of lavemisol,Vaproic acid. Endogenous Source: • Human disease arises from disturbance of the normal biochemical processes. A logical therapeutic approach is the administration of one or more of these naturally occurring endogenous molecules or their analougues.The most important approach under this source is Peptidomimetic Chemistry using non-peptides to mimic endogenous peptide activity. Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies Preclinical studies Clinical Trials
- 23. Continued… Exogenous Source: (Ethanobotanyor Ethanopharmacology) • The molecules which are endogenous to the other life form such as plants and animals but do not occur naturally within human body ,such molecules are classed as exogenous molecule for prospective of drug designing for human beings Rational Drug Design • Approximately 2000 small molecules that theoretically exist in our world out of which 1052 are drug like molecules and many of which are purely synthetic and cannot occur naturally. Thus there is an opportunity to explore the none naturally occurring synthetic compounds as potential source of lead compound
- 24. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening Continued… 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
- 25. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening Continued… High throughput screening • It refers to the process by which pharmaceutical companies are able to obtain initial screening data up to 1 million compounds testing against as many as 50 different biological targets/years. This expansion of data collection by several orders of magnitude is primarily due to advancement in Robotics, combinatorial chemistry and instrumentation. • Screening of drug target against selection of chemicals. • Identification of highly target specific compounds.
- 26. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Assay Development • Used for measuring the activity of a drug. • Discriminate between compounds. • Evaluate: • Expressed protein targets. • Enzyme/ substrate interactions. Synthesis and Isolation Combinatorial Chemistry Assay Development High Throughput Screening
- 27. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Library Development SAR Studies In Silico Screening Chemical Synthesis MEDICINAL CHEMISTRY • It’s a discipline at the intersection of synthetic organic chemistry and pharmacology. • Focuses on small organic molecules (and not on biologics and inorganic compounds) • Used in • Drug discovery (hits) • Lead optimization (hit to lead)
- 28. Target Selection Lead Discovery Medicinal Chemistry InVitro 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
- 29. Target Selection Lead Discovery Medicinal Chemistry InVitro 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
- 30. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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. • Economic than HTS
- 31. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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
- 32. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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)
- 34. PRECLINICAL STUDIES • Theaim of this stage is to satisfy all the requirements that have to be met before a new compound is deemed ready to be tested for the first time in humans. The work falls into four categories • Pharmacological testing • Preliminary Toxicological testing • Pharmacokinetics studies i.e ADME studies • Chemical and pharmaceutical assessment to assess the feasibility of large scale synthesis and purification. Animal models of Disease States Behavioural Studies Functional Imaging Ex-Vivo Studies Target Selection Lead Discovery Medicinal Chemistry In Vitro Studies Preclinical studies Clinical Trials
- 35. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Animal models of Disease States Behavioural Studies Functional Imaging Ex-Vivo Studies PRECLINICAL STUDIES • Its experimentation using a whole, living organism. • Gives information about, • Metabolic profile • Toxicology • Drug interaction
- 36. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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
- 37. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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.. • Example: • Despair based- Forced swimming/ Tail suspension • Reward based • Anxiety Based
- 38. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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 are used • MRI • CT-Scan
- 39. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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
- 40. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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.
- 41. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical 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
- 42. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Phase-I Phase-II Phase-III Phase-IV Phase II: • Controlled Clinical Evaluation. • 50-300 Patients • Controlled Single Blind Technique • Concerned With: – Safety – Efficacy – Drug Toxicity&Drug Interaction
- 43. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Phase-I Phase-II Phase-III Phase-IV Phase III: • Extended Clinical Trials. • Most expensive & time consuming. • 250-1000 Patients. • Controlled Double Blind Technique. • Concerned With: – Safety, Efficacy – Comparison with other Drugs – Package Insert
- 44. Target Selection Lead Discovery Medicinal Chemistry InVitro Studies Preclinical studies Clinical Trials Phase-I Phase-II Phase-III Phase-IV Phase IV: • Post Marketing Surveillance. • Designed to detect any rare or long-term adverse effects. • Adverse Drug Reaction Monitoring
- 46. ABSTRACT 1 • Areview article highlight the use of genomics and proteomics in pharmaceutical drug discovery and development stating that One of the most pressing issues facing the pharmaceutical industry is the tremendous dropout rate of lead drug candidates. Genomics and proteomics are today well established in drug discovery and development, in combination with combinatorial chemistry and high-throughput screening, are helping to bring forward a matchless number of potential lead compounds. Over the last two decades, several new genomic technologies have been developed in hopes of addressing the issues of target identification and lead candidate optimization. Proteomics is a technology platform that is gaining widespread use in drug discovery and drug development programs. Defined as the protein complement of the genome, the proteome is a varied and dynamic repertoire of molecules that in many ways dictates the functional form that is taken by the genome. We focus in this article on recent progress and innovations utilizing “omics” technologies to identify and validate drug targets, discover disease biomarkers, and design more effective drugs.( SHARMA NEHA and HARIKUMAR S.L,2013)4
- 47. ABSTRACT 2 • Astudy carried out by Abdul Wadood et al(2014) on the in silico technique illustrates that Hepatitis C virus (HCV) infection is an alarming and growing threat to public health. The present treatment gives limited efficacy and is poorly tolerated, recommending the urgent medical demand for novel therapeutics. NS3/4A protease is a significant emerging target for the treatment of HCV infection. This work reports the complex-based pharmacophore modeling to find out the important pharmacophoric features essential for the inhibition of both protease and helicase activity of NS3/4A protein of HCV. A seven featured pharmacophore model of HCV NS3/4A protease was developed from the crystal structure of NS3/4A protease in complex with a macrocyclic inhibitor interacting with both protease and helicase sites residues via MOE pharmacophore constructing tool. It consists of four hydrogen bond acceptors (Acc), one hydrophobic (Hyd), one for lone pair or active hydrogen (Atom L) and a heavy atom feature (Atom Q). The generated pharmacophore model was validated by a test database of seventy known inhibitors containing 55 active and 15 inactive/least active compounds. The validated pharmacophore model was used to virtually screen the ChemBridge database. As a result of screening 1009 hits were retrieved and were subjected to filtering by Lipinski’s rule of five on the basis of which 786 hits were selected for further assessment using molecular docking studies. Finally, 15 hits of different scaffolds having interactions with important active site residues were predicted as lead candidates. These candidates having unique scaffolds have a strong likelihood to act as further starting points in the development of novel and potent NS3/4A protease inhibitors.( Abdul Wadood,et al,2014)6
- 48. ) RECENTLY APPROVED DRUGS BYFDA(2014
- 49. Generic Therapeutic Use Testosteroneundecanoate Treatment of hypogonadism Dapagliflozin Type II diabetes Droxidopa Neurogenic orthostatic hypotension Ibrutinib Chronic lymphocytic leukemia Tasimelteon Non-24-hour sleep-wake disorder