Drug Design: Computer Aided

Question 0

What are the different parameters that can be calculated using the schrondinger equation?

Answer 0

Molecular descriptors
Docking-scoring
Molecular mechanics - dynamics
Semi emperical methods
Density function th.
Cc

Question 1

What are the advantages and disadvantages of the schrondinger equation?

Answer 1

+ can be used to calculate anything in chemistry

- can only be applied to small systems like H. This is smaller than many biological systems

Question 2

What is the driving force for use of computers?

Answer 2

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.

Question 3

What are the advantages and disadvantages of molecular descriptors?

Answer 3

It is a simple method, but does not have a very good prediction power

Question 4

What is the equation Eff = Estr + Ebend + Etors + Evdw + Eele

Answer 4

This is easy to calculate on the computer and good for looking at complex systems

Question 5

What is electron affinity?

Answer 5

The amount of energy required to add an electron to the molecule. This does not correlate well experimentally and theoretically

Question 6

What is significant about the log P parameter?

Answer 6

It correlates quite well experimentally and theoretically with a strong relationship of R = 0.963

Question 7

What is chemoinformatics ?

Answer 7

The Molecular descriptors such as

• lipski’s rule of 5
• rotatable bonds </= 140 angstrom squared

Question 8

What have molecular descriptors taught us?

Answer 8

E.g. In the case of log p, if a compound istoo lipophilic it acts at many different compounds in proteins

Question 9

What are the two main types of molecular descriptors?

Answer 9

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

Question 10

How are molecular descriptors used?

Answer 10

We use computer and experimentational data and an atom or fragment based approach to mathematically break down the molecule

Question 11

Why do the majority of drugs NOT have high dipole moments?

Answer 11

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

Question 12

Which molecular descriptors are most commonly used?

Answer 12

The mainstream ones such as log P as these are easy to understand

Question 13

What is the lead like chemical space?

Answer 13

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.

Question 14

Why is starting with a small molecule of MW < 300 and H bond < 3 desired?

Answer 14

There is more room to add things to

Question 15

Why do we look for similarity methods?

Answer 15

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.

Question 16

What is the main difficulty with similarity methods?

Answer 16

Similarity is subjective, however numerical descriptors have been developed to quantify similarity e.g. Bitstrings -> tanimoto coefficient

Question 17

What are bitstrings?

Answer 17

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

Question 18

What is the tanimoto coefficient?

Answer 18

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

Question 19

How was psychotropic drugs such as Li+ discovered?

Answer 19

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