drug discovery process-an overview

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prediscovery.target identification,target validation,early safety tests,lead identification

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By T.Vijaya Y11MPH475 Drug discovery process-an overview By T.Vijaya I/II M.Pharmacy-Pharmacology

What is a drug?: 

What is a drug? Chalapathi Institute Of Pharmaceutical Sciences 2 According to WHO Any substance or product that is used or intended to be used to modify or explore the physiological system or pathological state in the benefit of the recipient.

History: 

History Chalapathi Institute Of Pharmaceutical Sciences 3 Old medical texts from Mesopotamia (Iraq) describes over 1000 plant derived substances (2600 BC) Ancient Egyptians in their texts have described over 800 complex prescriptions (1500 BC) Charaka Samhita (900 BC) formed the basis of Ayurveda, described over 300 medicines Sushruta Samhita (600 BC) described various surgeries Traditional Chinese medicine (350 BC) described over 250 natural agents and complex prescriptions

Stages of development of new drug: 

Stages of development of new drug Chalapathi Institute Of Pharmaceutical Sciences 4

Drug discovery process: 

Drug discovery process Chalapathi Institute Of Pharmaceutical Sciences 5 Pre-discovery Target identification Target validation Drug discovery Early safety tests Lead optimisation

Choosing a disease: 

Choosing a disease Chalapathi Institute Of Pharmaceutical Sciences 6 Pharmaceutical companies tend to concentrate on developing drugs for diseases which are prevalent in developed countries, and aim to produce compounds with better properties than existing drugs. Pharmaceutical companies have to consider economic factors as well as medical ones when they decide which disease to target when designing a new drug. Most research is carried out on ailments such as migraine, depression, ulcers, obesity, flu, cancer and cardiovascular disease.

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Chalapathi Institute Of Pharmaceutical Sciences 7 Prediscovery Target Identification Target Validation Understanding the disease Identify cellular and genetic factors Government, academia, industry Sequencing of human genome has significant impact Need to know which gene(s) are involved and how they interact Identify biological targets for the disease Target based approach identifies genes and proteins involved in disease Uses human genome Physiology based approach identifies responses using cell based or animal model Individual or combination of approaches used Ensure target is involved in disease In vitro tests performed to confirm that changing the target will result in a change in the disease In vivo tests performed with animals to confirm in vitro tests Results will help predict profile of new drugs and help determine if effective drugs can be made

Drug Discovery Process: 

Drug Discovery Process Chalapathi Institute Of Pharmaceutical Sciences 8

  Combinatorial Chemistry : 

Combinatorial Chemistry Chalapathi Institute Of Pharmaceutical Sciences 9 It is a collection of techniques which allow for the synthesis of multiple compounds at the same time. Principle of Combinatorial Chemistry: Generation of compound libraries from molecular building blocks which are usually used in HTS.

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10 Chalapathi Institute Of Pharmaceutical Sciences

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Conventional strategy Combinatorial strategy Chalapathi Institute Of Pharmaceutical Sciences 11 One molecule at a time Make purity test Hundreds of molecules per month Slower lead generation High risk of failure Many molecule at a time Make purity test Thousands of molecules per month Faster lead generation Lower risk of failure synergy Lead identification

History of Combinatorial Chemistry  : 

History of Combinatorial Chemistry Chalapathi Institute Of Pharmaceutical Sciences 12 Bruce Merrifield won the Nobel prize in chemistry in 1984 for his work on solid-phase synthesis. H. Mario Geysen distinguished research scientist at Glico Welcome Inc.,helped jump-start the field in 1984 when his group developed a technique for synthesizing peptides on pin-shaped solid supports. (currently, a faculty of Univ. of Virginia, Chemistry Department)

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Chalapathi Institute Of Pharmaceutical Sciences 13 Another early pioneer was Arpad Furka who introduced the commonly used split-and- pool methods. Bunin and Ellman’s seminal work on solid phase organic synthesis (SPOS) of arrays of 1,4-benzodiazepine-2-ones in 1992.

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Chalapathi Institute Of Pharmaceutical Sciences 14 Solid phase synthesis Solution phase synthesis The compound library have been synthesized on solid phase such as resin bead, pins or chips. The compound library have been synthesized in solvent in the reaction flask Small amounts of products formed Large amounts of products can be synthesised Simple isolation of products by filtration Work up & purification more difficult Require two extra reaction steps: linkage & cleavage No extra steps needed Limits chemistry which can be performed Wide range of reactions can be utilized Automation available Automation not as highly developed Large excess of reagent can be used to drive the reaction to completion Cannot use large reagent excess

Preparation of libraries: 

Preparation of libraries Chalapathi Institute Of Pharmaceutical Sciences 15 Parallel Synthesis: Coupling with building block A1-A3(1/3 of the resin beads for each building block), then washing, deprotection Coupling with building block B1-B3(1/3 of the resin beads for each building block), then washing, deprotection Coupling with building block C1-C3(1/3 of the resin beads for each building block), then washing, deprotection

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Chalapathi Institute Of Pharmaceutical Sciences 16 CONCEPT : Compounds are synthesized in parallel using spatially separated compartments One vessel -one compound“-philosophy Solid supported -as well as solution chemistry is possible Advantages: •Each compound is substantially „ pure“in its location •Defined location provides the structure of a certain compound •Easier biological evaluation Disadvantage: •Applicable only for medium libraries (several thousand compounds.

Pool/Split Synthesis : 

Pool/Split Synthesis Chalapathi Institute Of Pharmaceutical Sciences 17 Splitting of the resin, coupling with building block A1-A3 Pooling, washing, deprotection Splitting, coupling with B1-B3 Pooling, washing, deprotection Splitting, coupling with C1-C3

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Chalapathi Institute Of Pharmaceutical Sciences 18 After a Split-Pool-synthesis: just one single compound is bound to each resin bead one-bead-one-compound library Split-Pool-Procedure requires a solid support Advantages: Only few reaction vessels required Method of choice for large libraries (up to 105compounds) Disadvantages: Three fold amount of resin beads necessary Only little amounts of the synthesized compounds available

High Throughput Screening: 

High Throughput Screening Chalapathi Institute Of Pharmaceutical Sciences 19 HTS is the process by which very large numbers of compounds (hundreds of thousands) from a variety of sources such as synthetic compound collections, natural product extracts & combinatorial chemistry libraries are tested against biological targets.

Objectives: 

Objectives Chalapathi Institute Of Pharmaceutical Sciences 20

Essential components:: 

Essential components: Chalapathi Institute Of Pharmaceutical Sciences 21 Targets Assays Compound libraries Automation Information systems Facilities Scientists.

Technologies for HTS: 

Technologies for HTS Chalapathi Institute Of Pharmaceutical Sciences 22 Dispensing technologies: The piezo & ink jet systems The air displacement systems The pin tool systems Cell based assays Alternatives to in vitro biochemical assays for HTS Second messenger assays Reporter gene assays Cell proliferation assays Detection methods Fluorescence based assay technologies

Automation of HTS: 

Automation of HTS Chalapathi Institute Of Pharmaceutical Sciences 23 Automation may be defined as the use of stand alone instrumentation (work stations) that perform a given task whereas robotics use a robot arm or track systems to move micro plates between these instruments. HTS methods are used to characterize metabolic & pharmacokinetic data of new drugs.

Pharmacogenomics: 

Pharmacogenomics Chalapathi Institute Of Pharmaceutical Sciences 24 Deals with influence of genetic variation on drug response in patients by correlating gene expression with drug’s efficacy or toxicity. Impact of Genetics/Genomics on Drug Discovery Mining genetic sequence databases Monitoring gene expression patterns during disease/drug treatment Model organisms

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Chalapathi Institute Of Pharmaceutical Sciences 25 In today’s world, only 30-60% of drugs work effectively to rid of a patients illness. However with the application of pharmacogenomics the success rate of drugs will increase to 100% curing all patients.

Proteomics: 

Proteomics Chalapathi Institute Of Pharmaceutical Sciences 26 Definition: The analysis of the entire protein complement expressed by a genome, or by a cell or tissue type.

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Chalapathi Institute Of Pharmaceutical Sciences 27 Two most applied technologies: 2-D electrophoresis: Separation of complex protein mixtures Mass spectrometry: Identification and structure analysis Applications: Protein identification Protein Expression Studies Protein Function Protein-Protein Interactions Target/marker identification Target validation/toxicology

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Chalapathi Institute Of Pharmaceutical Sciences 28

Micro array technology: 

Micro array technology Chalapathi Institute Of Pharmaceutical Sciences 29 Applications: To measure the expression patterns of thousands of genes in parallel ,generating clues to gene function that can help to identify appropriate targets for therapeutic intervention. To monitor changes in gene expression in response to drug treatments. In the study of differential gene expression in disease. Microarrays are potentially powerful tools for investigating the MOA In the long term microarrays will contribute the analysis of metabolic pathways.

Early Safety Tests: 

Early Safety Tests Chalapathi Institute Of Pharmaceutical Sciences 30 Lead compounds go through a series of tests to provide an early assessment of the safety of the lead compound. Scientists test ADME/Tox properties of each lead. Successful drugs must be: Absorbed into the bloodstream Distributed to the proper site of action in the body Metabolized efficiently and effectively Successfully excreted from the body Demonstrated to be not toxic.

Lead Optimization: 

Lead Optimization Chalapathi Institute Of Pharmaceutical Sciences 31 Lead compound: “A lead can be characterized as a compound that has some desirable biological activity, and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters” Objective: Increase potency/selectivity of the lead structure “Synthetic modification of a lead molecule to fulfill stereo electronic, physicochemical, pharmacokinetic and toxicologic properties required for clinical usefulness”

Goals and Concepts: 

Goals and Concepts Chalapathi Institute Of Pharmaceutical Sciences 32 Increasing potency and efficacy by A. Lipinski‘s rule of five B. Gradual modification of 3D shape and/or physicochemical properties C. Bioisosteric replacement of functional groups Improving physicochemical /ADME/Tox behaviour by A. Modification of physicochemical properties (e.g. lipophilicity, charge, flexibility etc.) B. Replacement of metabolically labile groups

Lipinski’s Rule-The rule of five: 

Lipinski’s Rule-The rule of five Chalapathi Institute Of Pharmaceutical Sciences 33 Poor absorption or permeation for oral small molecule are more likely when: There are more than 5 H-bond donors The molecular weight is over 500 The LogP is over 5 There are more than 10 H-bond acceptors Exception to the rule Antibiotics Natural products Vitamins Cardiac glycosides

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Summary: 

Summary Chalapathi Institute Of Pharmaceutical Sciences 35 The discovery process is currently on a steep growth curve both with respect to the number of targets & compounds to be screened & the complexity of the assays required. Combinatorial Chemistry as a valuable tool in drug discovery. HTS has become an increasingly sophisticated & important element in the drug discovery. Proteomics, genomics & micro arrays are used for target identification & target selection.

References: 

References Chalapathi Institute Of Pharmaceutical Sciences 36 Screening methods in pharmacology N.S.Parmar Shiv Prakash Pg.No.3-35 Drug discovery and evaluation H.Gerhard Vogel Pharmacological Assays second addition Pg.No.1-21 www.innovation.org

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