Drug Design Intro Flashcards
What are the main causes of death?
Heart 37%
Cancer 22%
Diabetes 2% Suicide murder 2% Lung - non cancer 3% Accidents 5% Brain 7%
Other 22%
What is the drug discovery pathway?
Biological target identified High throughput screening utilised Medicinal chemistry testing, drug molecular pharmacokinetic testing, Confirmation of biological target Clinical trials
What are the main ways of lead compound discovery?
Ethnopharmacology (aspirin from willow bark)
Screening of natural sources (plants, venoms, sea creatures and soil bacteria)
Combinatorial methods + screening (high throughput screening)
Virtual screening for lead structures
Serendipity (penicillin and Viagra)
Why do we not use lead compounds as drugs?
Most lead compounds are unsuitable for clinical use due to being
Not active enough
Having serious or undesired side effects
Not easily administered to patients -> not orally active
What is the effect of structural changes to a lead compound?
Structural changes can often alter pharmacological action and improve a particular activity or eliminate side effects.
E.g. Salicylic acid isolated from white willow had good painkiller properties but caused internal bleeding. After being structurally changed to salicylic, there were no undesired side effects while retaining the good painkiller property.
What does a lead structure provide?
A basis for the design of new drugs
What is neighbourhood behaviour?
Where structurally similar molecules tend to have similar properties e.g. Morphine, codeine and heroin
What is the correlation of structure with biological activity known as?
The structure activity relationship
What happens during an SAR study?
A number of compounds are made which vary slightly from the original and the biological activity of each one determined
What is the aim of a SAR study?
To determine which parts of the lead molecule are essential for biological activity and which parts cause undesired side effects
To develop an analogue of the lead co mound that has the best combination of therapeutic properties
What was the very first drug discovery programme based on a SAR approach?
The syphilis cure, Salvarsan which was discovered by Paul Ehrlich in 1910.
The lead compound was Atoxyl. This cured syphilis but was toxic. After 606 analogues were made, eventually Salvarsan aka Arsphenamine was made. This cured syphilis and was much less toxic.
What is the basis behind the synthesis of analogues for SAR studies?
There is no strategy or rationale behind these synthesis’
Where are SAR studies used?
Commonly in the industry and academia
Identification of all new binding groups in the lead compound can lead to discovery of the pharmacophore
What is a pharmacophore?
Contains only the relevant groups that interact with a receptor and are responsible for the activity
How are SARs used to determine pharmacophores?
Lead structure is identified
Possible drug target binding groups are identified
Synthesis of a series of analogues where only one binding group is removed is created (if the bioactivity is much lower after modification we know that the functional group is important and all analogues must contain it.
All analogues are tested for biological activity
The pharmacophore is identified