Molecular Modelling and Computing in Drug Design 2 (DONE) Flashcards
What are the four approaches to drug design where the structure of the target is known?
GRID based
Docking methods
Automated design
Intuition
What is GRID based methodology?
Programmes which investigate how and where chemical functionality binds in the active site
GRID is a programme where the active site of an enzyme is tested with various probes
For each probe at each position the energy is calculated
How can information from GRID be used in drug design?
To modify existing substrates or inhibitors, or to design inhibitors from scratch
How were influenza compounds investigated with GRID?
Sialidase is an enzyme thought to be involved in the formation of new virions, by cleaving sialic acid residues from several glycoproteins
The crystal structure of the enzyme with sialic acid has been solved
By examining the active site with GRID, this allowed understanding of interactions between the substrate and the active site
What are docking methods?
These are methods for seeing how well potential drugs fit in the active site of a target
Used to search a 3D database of small molecules and score how well they fit in the active site
Quality of the results depends on the scoring methods and on the flexibility of the system
Identification of novel anti-CHKV compounds
Viral illness transmitted by mosquitoes
A viral protease plays a key role in the infection, inhibition of this protease is a potential way to treat this disease
A model of the enzyme was built by homology modelling
What are automated structure construction methods?
De Novo design based on knowledge of the active site of the enzyme/ receptor
These programmes will design an appropriate ligand/ inhibitor starting from the structure of the active site
Large number of programmes
What are the two basic methods of automated structure construction methods and how do they work?
Connection of different atoms
Connection of different fragments
Either user or computer specifies a starting atom or chemical group(seed) in the active site, new atoms or fragments are then added randomly onto the seed
The new system is then evaluated and poor structures discarded
The user can define the properties of the molecule to be designed
What are the problems with de novo drug design?
Designs inhibitors without reference to how easy they are to make
Does not take into account the protein flexibility
Good design depends on the size and nature of the fragment library
Interactive drug design
To exploit human competence at its full it is necessary to provide the user with an interface that could give the ability to interact in realtime with the computer, adding the user knowledge and intuition directly into the ongoing simulation
What is a pharmacophore?
The relevant three dimensional orientation of essential functionalities required for biological activity
Features of the pharmacophore may include the following:
H bond donors/ acceptors
Hydrophobic regions
Aromatic regions
Charged groups
