Redecke Flashcards
The Definition of a Drug
A Drug is any substance that, when injected, inhaled,smoked, consumed, absorbed via a patch on the skin, or dissolved under the tongue, causes a physiological change in the body.
What kind of bioaktivem molecules can be considered as drugs?
- small molecules
- peptides
- peptidomimetics
- protein
- oligonucleotides
Gleevac
Chronic myeloid leukaemia (CML)
Inhibitor of ATP binding site of bcr-abl tyrosine kinase
Philadelphia chromosome
Lipitor
Cardiovascular disease
Statin (lipid lowering agent)
HMG-coA reductase inhibitor
Bestselling drug sofar
Taxol
Pacific yew tree bark extract
Ovarian and breast cancer
Stabilises microtubuli
Cell culture production
Viagra
Hypertension/ erectile dysfunction
inhibition of cGMP specific phosphodiesterase
lifestyle drug
Harvoni
Hepatitis C virus infection
Combination of Ledipasvir and Sofosbuvir
NS5A and NS5B inhibitors
-mabs
monoclonal antibodies eg. Adalimumab, Infliximab (immune suppressor TNF-a)
autoimmune disorders
Paul Ehrlich
-conceived many of the key elements of modern drug discovery
-salvarsan 1. cure for syphilisis
-from organic dyes to first discovered resistance rugs
recognition of chemicals for therapy - targeted chemotherapy
used synthetic chemistry to make derivates with different activities
recognized that metabolism could modify chemicals internally - active metabolite concept (pro drug)
Prontosil
Azo dye that becomes wold first broad-spectrum anti-biotic
What is rational drug design?
Rational (mechanism-based) drug discovery first identifies a key molecular target (drug-receptor) that is important in the disease process
How do molecules act that are interesting for rational drug discovery?
- Block BINDING of endogenous ligand
- Inhibit ACTIVITY of the target
- Alter EXPRESSION of the target
- Alter INTERACTION of the target with other molecules
Name the steps of rational drug discovery
- Disease selection
- Target identification
- Lead compound identification
- lead compound optimization
- Pre-clinical trials
- Clinical trials
Name characteristics of a good target
A good target..
-is efficacious and save
-meets clinical and commercial needs
-is druggable (accessible to putative drug molecules)
-has specific binding sites
-may change its biomolecular structure upon small molecule binding
-induces a physiological response by structure change on cell, organ or body level
-phsycological responses have therapeutic effect on pathological conditions
BUT
-drug targets are also involved in physiological processes
-complicated diseases - many different drug targets in a disease
-drug targets can change
drug might have more then one target
Target identification methods
- Data mining: Use of bioinformatics and databases (genomics, transcriptomics, proteomics, structures, literature, etc.)
- Structural genomics: sequence-structure homology recognition (fold recognition)
- Cell or animal models: studying the disease (tumor cell line, diabetic mice..)
Target validation
-> verifying the role in the disease
-defining the role of the target in the disease
-identifying patient populations susceptible to intervention using the target
-performing experiments in a cellular system to confirm that regulation of the target or downstream effects have the expected effect
=> Target validation confirms that interactions with the target produce the desired change in the behaviour of diseased cells
Assay development
Screening = Filtration of active molecules against a target from a huge library
- enable characterization of novel compounds and obtain the potency of these compounds against the target in question
- robot-assisted HTS
Strategy lead discovery/ optimization:
Pros and cons of High-throughput screening (HTS)
\+ no structural info needed robot-assisted libraries of compounds - enormous chemical space false positive hits expensive
Strategy lead discovery/ optimization:
Pros and cons of virtual screening
\+ structure-guided optimization low costs fragment libraries - computational capacity adequate scoring factor based on predicted interactions
Strategy lead discovery/ optimization:
Pros and cons of Structure based drug discovery (SBDD)
\+ structure-based optimization fragment libraries no false positive low binding affinities - requires crystal of protein complex high-throughput screening? expensive
