Altklausuren Flashcards
Briefly describe the process of virtual drug screening. In addition, describe the advantages and disadvantages of the virtual screening approach compared to the structure-based drug discovery (SBDD) approach.
Virtual drug screening is based on computational techniques to search libraries of small molecules to identify those structures which are most likely to bind to a drug target. In order to do this the 3D structure of the target protein must be known. The molecular docking on the 3D target receptor is being performed in silico. This docking is limited to restricted zones. The adequate scoring function is essential, based on predicted interactions. This method may improve the likelihood of finding a good compound.
Both methods need the 3D structure, and fragment libraries and use structure-guided optimizations. Virtual screening is a low-cost method compared to SBDD. SBDD has no false positives and low binding affinity but needs a crystal of protein complex. Virtual screening lacks an adequate scoring function and is just based on predicted interactions.
Briefly describe the process of Structure-based drug discovery (SBDD). Please mention the individual steps of the process with a focus on SBDD. Furthermore, describe the advantages and disadvantages of the SBDD approach compared to other approaches
- Disease selection
- Target selection
- Target identification - 3D structure identification via x-ray crystallography e.g. of the target compound identification via virtual screening if no ligands are known or fragment-based lead discovery using fragment libraries, performing co-crystallography or soaking of these libraries
- lead optimization based on the structural data from the steps before
- Pre-clinical trials
- Clinical trails
There are different approaches to optimize a fragment, which was identified as a ‘hit’, e.g. by applying high-throughput screening of fragment libraries together with x-ray crystallography, into a lead structure. Briefly describe in this context the ‘fragment self-assembly’ approach.
Strategies for fragment-based lead discovery:
- Fragment evolution: An initial fragment hit identified by HT crystallographic screening. Fragment is evolved or iteratively built out from the starting fragment to create larger, more complex molecule that interacts with neighboring pockets.
- Fragment linking: High-throughput rytallographic fragment screening identifies different fragments bound to adjacent pockets in the active site. Fragments are joint with chemical linker, leading to a larger molecule with higher binding affinity.
- Fragment optimization: lead molecule generated from fragments is rationally re-engineered over several steps in order to improve or alter specific properties of the molecule (affinity, selectivity, oral bioavailability..)
- Fragment self-assambly (most favored) : Chemically reactive mixtures of fragments (dynamic combinatorial libraries) link together when situated in close proximity in an active site. Target catalyses the synthesis of its own lead from the library fragments. Dynamic combinatorial x-ray crystallography (DCX) allowes seld-assembled leads to be generated in the presence of crystals, permitting direct observation of binding interaction with the target.
The identification of a suitable target represents an essential step in the rational drug design process. Present at least four properties that characterize a good and suitable target in headwords.
A good target..
- is efficacious and save
- meets clinical and commercial needs
- is ‘druggable’
- 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
- physiological responses have a therapeutic effect on pathological conditions
The identification of a suitable target represents an essential step in the rational drug design process. Briefly describe a strategy how to identify a good drug target in infectious diseases. Which techniques/approaches would apply for target identification? Furthermore, please present at least four properties that characterize a good and suitable target in headwords!
Target identifiaction: Identification of a protein (enzyme/receptor) or gene associated with the disease that could be modulated by drug interation.
Taget discovery: Identification + Validation + Characterisation.
Approches:
- molecular approach: identification of intracellular targets via clinical samples (genomics, proteomics, gene association) - correlative method
- system approaches: when phenotype is detected at organismal level via cell, animal models or in patients. Cell model via forward genetics, animal model via reverse genetics, patients via clinical research - 3 combined classified as phenotype based models
+ data mining
Why is Relenza not suitable for oral adminitration?
Relenza has no lipophilicity like Tamiflu
Which functional group renders Tamiflu a prodrug?
The COOEt, Ester group because of esterases within the cell
Without knowing anything about the structural detail of the inhibitor bound to viral neuraminidase, which structural feature would lead us to expect that Tamiflu binds with higher affinity to the enzyme than Relenza? How can you rationalize your answer?
keine Ahnung
The development of statins over the years is a good example for how to optimize drugs thermodynamically. Explain in a few sentences why it is important to increase the binding enthalpy of a drug.
In addition to optimizing the thermodynamics of a binding reaction, there is another set of parameters characterizing binding that need to be within certain ranges. What kind of parameters are these?
Different contact forms like vdW or H bonds contribute differently to the protein-ligand interaction. By increasing the entalphy one also stabilizes the molecule. Optimization of the thermodynamics of the binding reaction
the binding potency is a function of two quantities. Maximal potency is achieved when both the enthalpy and entropy changes contribute favouraby to binding. Entropy is easy to optimize, enthalpy is difficult.
A researcher claims that he has found a small-molecule inhibitor for carbonic anhydrase, which is a prominent therapeutic target in cardiovascular disease. The compound has a Ki value of 1mM, a molecular weight of 700 Da and a log P value of 6. Convince you colleague that this compound does not yet qualify for therapeutic purposes. To do so give two strong arguments against the use of this compound as an orally applicated drug.
The Ki is quiet high - probably no specific binding. In addition saturation of the target is only acivable if the patient takes a bis amount of the compound. THe log P is high (rule of 5) - very poor solubility.
Molecular weight is over 500 (rule of 5)
For Fluvastatin a free enthalpy binding to HMG-coA reductase of dG= - 9.0 kcal/mol has been determined at 310K ITC experiments yield no entalphy changes upon binding. Calculate the etropic contribution -TdS
Calculate the dissociation constant K0 fot this binding reaction
dG= dH-TdS -TdS = dG+ dH = - 9.0 + 0.0 = -9.0 kcal/mol
K=RTln(dG)
=8,314 J mol^-1 K^-1 (1/4,184 kcal/J)310Kln(9)
=0,45 uM
Organic compounds containing sulfoxides (S=O) are structurally very different from Ketones (C=O). Explain the difference between the two classes of molecules using wedge stroke formulas.
S
