Summary of the entire course Preclinical Drug Research (18/20): This is a compact summary of the whole course from the subject Preclinical Drug Research (slides, lectures, and all the important information from the insert) & elaboration of all the old exam questions from the course Preclinical Drug...
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Summary
preclinical drug
research
2018
Semester 1 2020-2021
1st Master Biomedical sciences
University of Antwerp
1
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Table of contents
Inhoud
Table of contents .............................................................................................................................................................................................. 2
Exam information .............................................................................................................................................................................................. 7
1 Introduction to drug R&D and the pharmaceutical industry ................................................................................................................... 8
1.1 Introduction............................................................................................................................................................................... 8
1.2 Some facts and figures ............................................................................................................................................................. 8
1.3 Development costs and revenue cycle...................................................................................................................................... 9
1.4 Timelines of drug development ............................................................................................................................................... 11
1.5 Challenges for the pharmaceutical industry ............................................................................................................................ 12
1.6 Product positioning ................................................................................................................................................................. 13
1.7 Failure rates in drug development ........................................................................................................................................... 13
1.8 Drug targets............................................................................................................................................................................ 14
1.9 Biotech-derived medicines ...................................................................................................................................................... 15
1.10 Major pharmaceutical companies ........................................................................................................................................... 15
2 Drug discovery process ...................................................................................................................................................................... 19
2.1 Therapeutic modalities............................................................................................................................................................ 19
2.1.1 Types of therapeutics .................................................................................................................................................... 19
2.2 Current therapeutics ............................................................................................................................................................... 19
2.2.1 Conventional therapeutic drugs ..................................................................................................................................... 19
2.2.2 Biopharmaceuticals....................................................................................................................................................... 20
2.3 General principles of drug discovery process .......................................................................................................................... 22
2.3.1 Introduction ................................................................................................................................................................... 22
2.3.2 Current trends in drug discovery ................................................................................................................................... 24
2.4 Selection criteria for oral drug candidate (in early discovery phase) ........................................................................................ 24
2.4.1 Chemical characteristics ............................................................................................................................................... 24
2.4.2 Pharmacological ........................................................................................................................................................... 25
2.4.3 Pharmacokinetic ........................................................................................................................................................... 25
2.4.4 toxicological .................................................................................................................................................................. 25
2.5 Choosing the project ............................................................................................................................................................... 25
3 Target identification and validation ..................................................................................................................................................... 27
3.1 Drug target interaction ............................................................................................................................................................ 27
3.2 Strategies for finding new drug targets.................................................................................................................................... 28
3.2.1 Conventional strategies to find new drug targets ........................................................................................................... 28
3.2.2 New strategies for drug target identification .................................................................................................................. 29
3.2.3 New strategies for drug target validation ....................................................................................................................... 30
4 Lead finding and lead optimization (drug screening) ........................................................................................................................... 32
4.1 Introduction............................................................................................................................................................................. 32
4.2 Definitions............................................................................................................................................................................... 33
4.2.1 Hits ............................................................................................................................................................................... 33
4.2.2 Leads ............................................................................................................................................................................ 33
4.3 The drug candidate ................................................................................................................................................................. 34
4.4 Lipinski’s rule .......................................................................................................................................................................... 34
4.5 Hit and lead identification ........................................................................................................................................................ 35
2
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4.5.1 Random (high throughput screening of compound libraries ........................................................................................... 35
4.5.2 Knowledge-based ......................................................................................................................................................... 35
4.6 Drug screening technologies .................................................................................................................................................. 35
4.6.1 Background .................................................................................................................................................................. 35
4.7 Practical: high throughput methods and set up ....................................................................................................................... 36
4.7.1 Compound logistics....................................................................................................................................................... 36
4.7.2 Assay development....................................................................................................................................................... 36
4.7.3 Automated screening .................................................................................................................................................... 36
4.7.4 Assay validation in high throughput .............................................................................................................................. 36
4.8 Screening assay types............................................................................................................................................................ 37
4.8.1 Cell-free in vitro system................................................................................................................................................. 37
4.8.2 Cell-based in vitro system ............................................................................................................................................. 39
4.9 Lead structure requirements ................................................................................................................................................... 40
4.9.1 Suitable molecular properties ........................................................................................................................................ 40
4.9.2 Favorable pharmacodynamics ...................................................................................................................................... 40
4.9.3 Acceptable pharmacokinetics........................................................................................................................................ 40
4.9.4 Chemical optimization potential..................................................................................................................................... 40
4.9.5 Patentability .................................................................................................................................................................. 40
5 Pharmacokinetics in drug discovery.................................................................................................................................................... 41
5.1 Introduction............................................................................................................................................................................. 41
5.2 Basics of pharmacokinetics .................................................................................................................................................... 42
5.2.1 Absorption .................................................................................................................................................................... 42
5.2.2 Distribution.................................................................................................................................................................... 43
5.2.3 Metabolisation............................................................................................................................................................... 44
5.2.4 Elimination .................................................................................................................................................................... 46
5.2.5 Steady-state.................................................................................................................................................................. 47
5.2.6 One-compartment model .............................................................................................................................................. 47
5.2.7 Two-compartment model .............................................................................................................................................. 47
5.3 Drug transporters.................................................................................................................................................................... 48
5.4 Drug properties and PK characteristics ................................................................................................................................... 49
5.5 Determining the plasma concentration of your drug ................................................................................................................ 50
5.6 In silico prediction of DMPK properties ................................................................................................................................... 51
5.7 Physicochemical properties .................................................................................................................................................... 52
5.7.1 Charge state ................................................................................................................................................................. 52
5.7.2 Lipophilicity ................................................................................................................................................................... 52
5.7.3 Aqueous solubility ......................................................................................................................................................... 53
5.8 In vivo pharmacokinetics ........................................................................................................................................................ 53
5.8.1 Exploratory pharmacokinetics ....................................................................................................................................... 53
5.8.2 Whole body autoradiography ........................................................................................................................................ 53
6 Pharmacology .................................................................................................................................................................................... 54
6.1 Introduction............................................................................................................................................................................. 54
6.2 Screening for selectivity (in vitro) ............................................................................................................................................ 56
6.2.1 Saturation assay ........................................................................................................................................................... 56
6.2.2 Displacement assay ...................................................................................................................................................... 57
6.3 Pharmacological profiling ........................................................................................................................................................ 57
6.3.1 In vitro profiling on isolated tissues................................................................................................................................ 57
3
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