MDD Overview Flashcards
what is a patent?
A legal protection of a discovery
How long can a patent last for?
20 years
What are the first ten years in industry spent doing?
research!
How can a patent be extended? if so how long for?
can be extended up to another 5 years under a supplementary protection certificate if the drug has been found to be viable for a new indication
- What do we do if there is no known 3D Structure and No known ligands !?
Combinatorial chemistry can be used to make several thousand compounds in a single process.
High throughput screening - biological assay of a large number of chemicals
What can be done if there is no known 3D structure, BUT the ligands are known
We do a pharmacophore search and QSAR studies
What do we do if the 3D stucture is known but the ligands are not known?
De novo design - build a ligand based on 3D structure.
Virtual Screening - using computer based models to identify molecules that are most likely to bind to an enzyme or a receptor
What do we do if the 3D stucure is known and the ligands are known?
Structure based design
Combinatorial chemistry can be used to make several thousand compounds in a single process.
High throughput screening - biological assay of a large number of chemicals
- What do we do if there is no known 3D Structure and No known ligands !?
We do a pharmacophore search and QSAR studies
What can be done if there is no known 3D structure, BUT the ligands are known
De novo design - build a ligand based on 3D structure.
Virtual Screening - using computer based models to identify molecules that are most likely to bind to an enzyme or a receptor
What do we do if the 3D stucture is known but the ligands are not known?
Structure based design
What do we do if the 3D stucure is known and the ligands are known?
State 6 key principles of drug design (6marks)
- Drugs and receptors must have complimentary distribution of functional groups to maximise Hydrogen bonding and Electostatic interactions
- Hydrogen bonds have a specific role to play in specificity (binding) but not affinity (attraction)
- Charged groups have a significant role to play in both specificty and affinity
- Drugs must have a complimentary size and shape to maximise VDW
- VDW has a contribution to affinity but not specificity
- Conformationally constrained molecules are more likely to be potent than unconstrained ones
what problems are associated with drug design?
the drug should be cheap (but isnt)
chemically stable
should be potent
lipophillic but still water soluble
stable against enzymes
How to improve drug affinity?
You need:
- Large surface area of interaction
- Numberous hydrogen bonds and electrostatic interactions
- A drug with polar group, but not too polar where it is absorbed poorly.
write down gibbs equation of free energy
delatG = deltaH - TdeltaS
Where deltaH = enthalpy change
deltaS = change in entropy as a function of temperature
what is the entropy of a molecule defined by?
Defined by its freedom of translational, rotational movement and freedom of conformational change
What is the ideal characteristics for drugs in terms of entropy?
The drug-receptor complex must be enthalpically equivalent to the water-receptor complexes, so not to reduce entropy which is undesirable
The newly formed complex must also be enthalpically superior when the electrostatic interactions (if any) are made.
what is a lead compound? And state where they come from
- First compound or structural motif of a new family of therapeutic agents to be discovered.
- Rarely the actual drug structure that will be marketed or go to clinical trials
- Protected by patent
They Can be found by:
- Screening of synthetic or natural compounds (imatinib)
- Natural products (Aspirin)
- Side effects (viagra)
- Metabolism studies (estrogen)
- Serendipity (Penicillin)
- Rational Drug design (tramadol)
outline how to screen for hits:
First coose therapeutic area its ‘target’
target may be a protein or nucleic acid
choose and develop assay (High-throughput)
choose molecules form libraries too
carry out screen and analyse data for ‘hits’
develop ‘hit’ to ‘lead’ by chemical synthesis
what would we look for in a primary screen?
molecules that target the biological stuctures. e.g Enzyme-based, cell based etc used in a well
