Drug Design: Computer Aided Flashcards
What are the different parameters that can be calculated using the schrondinger equation?
Molecular descriptors Docking-scoring Molecular mechanics - dynamics Semi emperical methods Density function th. Cc
What are the advantages and disadvantages of the schrondinger equation?
+ can be used to calculate anything in chemistry
- can only be applied to small systems like H. This is smaller than many biological systems
What is the driving force for use of computers?
Saves money.
It is always cheaper to run a computer calculation than doing the actual experiment.
Conducting the actual experiment requires costs for training lab technicians, buying reagents, using the lab, using equipment etc.
What are the advantages and disadvantages of molecular descriptors?
It is a simple method, but does not have a very good prediction power
What is the equation Eff = Estr + Ebend + Etors + Evdw + Eele
This is easy to calculate on the computer and good for looking at complex systems
What is electron affinity?
The amount of energy required to add an electron to the molecule. This does not correlate well experimentally and theoretically
What is significant about the log P parameter?
It correlates quite well experimentally and theoretically with a strong relationship of R = 0.963
What is chemoinformatics ?
The Molecular descriptors such as
- lipski’s rule of 5
- rotatable bonds </= 140 angstrom squared
What have molecular descriptors taught us?
E.g. In the case of log p, if a compound istoo lipophilic it acts at many different compounds in proteins
What are the two main types of molecular descriptors?
1) Simple counts such as
MW </= 500 da,
H acceptors and H donators
Rotatable bonds
2) physicochemical properties (Atom or fragment based, emperical data ) such as
Log P
Dipole moments
Ionisation potentials
How are molecular descriptors used?
We use computer and experimentational data and an atom or fragment based approach to mathematically break down the molecule
Why do the majority of drugs NOT have high dipole moments?
They are not favourable as the drug needs to go through cell membrane therefore there if the dipole moment was very large, it would have no affinity to go into the lipid bilayer
Which molecular descriptors are most commonly used?
The mainstream ones such as log P as these are easy to understand
What is the lead like chemical space?
A relatively small area encompassed in drug like chemical space.
Lead compounds are what we start with from HTS which medicinal chemists like to add structures to.
Why is starting with a small molecule of MW < 300 and H bond < 3 desired?
There is more room to add things to
Why do we look for similarity methods?
They are rational. The similar property principle states that structurally similar molecules tend to have similar properties.
Neighbourhood behaviour: the extent to which small structural changes defined by a molecular descriptor are likely to lead to small property changes.
What is the main difficulty with similarity methods?
Similarity is subjective, however numerical descriptors have been developed to quantify similarity e.g. Bitstrings -> tanimoto coefficient
What are bitstrings?
Uses binary form (as read by a computer) to describe structures.
If there is no hydrogen moiety, we give it a 0
If there is a benzene ring we give it a 1
This results in a series of binary strings which describes our molecule
What is the tanimoto coefficient?
This gives a erasure of the number of fragments in common between molecules. This coefficient ranges from 0-1 SAB= C / A+ B+ C where A = amount of 1s in molecule A B = amount of 1s in molecule B c = amount of 1s in common
How was psychotropic drugs such as Li+ discovered?
By john f. Cade
Hypothesised that abnormal uric acid metabolism causes manic depressive disorder.
Injected uric acid into guinea pigs
Uric acid is highly insoluble
The most soluble form is lithium urate
In 1974 it was discovered that Li has a profound sedative effect.
Mogens schou, Danish medical doctor championed lithium a intro for clinical use
