Lecture 1 extra reading (structure-based drug design) Flashcards
More examples of drugs discovered from structure-based drug design
Tamiflu (flu virus)
Gleevec (chronic myeloid leukaemia)
Tarceva (cancer)
Key sources of 3D information for structure-based drug design
NMR
X-ray crystallography
Example of a compound identified from X-ray crystallography
Researchers in the US determined X-ray structures of the HIV reverse transcriptase enzyme in complexes with various antiviral drugs
On the basis of these structures they discovered diarylpyrimidines as inhibitors of this reverse transcriptase
Developed as potential AIDS treatments
How can the usefulness of X-ray crystallography be enhanced?
Using it in combination with other techniques
Techniques that can be used in combination with X-ray crystallography
SAR (structure-activity relationship) analysis
Molecular modelling
X-ray crystallography in combination with SAR analysis
Scientists in the US were able to develop novel hydroxamates as potent inhibitors of TNF-a converting enzyme (TACE), for potential use as anti-inflammatory agents
X-ray crystallography in combination with molecular modelling
Allowed researchers in the US to develop potent, selective chymase inhibitors where it had previously been notoriously difficult to develop an inhibitor that was orally active, potent and selective
Shortfalls of X-ray crystallography
It’s difficult to obtain X-ray structures of membrane proteins because they are hard to isolate
Approx. 25% of protein-coding genes code for membrane proteins so this is an important area for improvement
Novel approaches to facilitating X-ray crystallography of membrane proteins
Small-volume crystallisation
Automated crystal imaging
Current important trends in structure-based drug design
Fragment-based approaches
Using structure-based techniques to improve ADMET properties
Fragment-based drug design
Based on the screening of small fragments that contain one or more functional group motifs
These fragments bind weakly to the target but can be combined and elaborated on
i.e. the molecule is ‘built up’ from less complex molecules by increasing complexity and enhancing potency
Example of using structure-based drug design to improve drug ADMET properties
Astex solved the crystal structure of CYP3A4, which is the cytochrome P450 enzyme responsible for the metabolism of more drugs than any other P450 enzyme
Can use this structure to rationally design drugs that have longer lifetimes of action and are less toxic
Summary of structure-based drug design
Structure-based drug design has been growing steadily in popularity as the number of protein structures determined has increased and computational power has improved rapidly
It allows you to undertake drug discovery in a focused and hypothesis-driven way, meaning fewer compounds need to be made
