Creating the right chemistry

The long and often looping road from hit to pre-clinical candidate.

The compounds we identify as hits in the initial target or phenotypic screens are not potential medicines for a person to take but are prototypes requiring substantial refinement. Being able to kill the parasite is far from the only property required for a hit to be able to progress to the clinic. The compound also needs to get to the part of the human body where the parasites live. It needs to stay there long enough to kill the parasite. It needs to kill the parasites without giving the patient unwanted side effects.

Turning the hit into a more medicine-like version (compound optimisation) can take many rounds of designing, making and testing new chemical compounds. The Design-Make-Test cycle. Compounds that pass the researchers’ tests are called ‘lead’ compounds. Chemists create a set of compounds related to the lead (a compound series). This allows the chemists to understand how different chemical modifications, that change the shape of the compound, change how the compound binds to its target protein and its properties. We call this building a structure-activity-relationship, SAR.

The compound series that give the best balance of activity and properties proceed to lead optimisation. The scientists design, make and test further modifications until they have a single compound with the correct balance of ability to kill the parasites and therefore cure the patient, while minimising side-effects. This is known as a ‘pre-clinical candidate’. The pre-clinical candidate undergoes further safety studies. It also undergoes further development in which it is mixed with other substances to turn it into a pill. If it passes these steps it will enter clinical trials, starting with safety studies in human volunteers. The Wellcome Centre for Anti-Infectives Research and DDU do not directly carry out clinical trials. We partner with other organisations who have the expertise and resource to run clinical trials.
It can take several years to go from the initial hit to a pre-clinical candidate. At WCAIR we are developing and bringing on board innovative methods and technologies that allow us to work smarter and faster. We aim to reduce the time to deliver a pre-clinical candidate and to provide stronger evidence that it will be an effective medicine.

Read more about out some of our projects in the following areas

Computer driven innovation

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High-throughput chemistry

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