Universiteit Leiden

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Leiden Early Drug Discovery & Development

Hit and Lead Optimization

The goal of hit and lead optimization is to optimize suitable chemical starting points that can modulate a drug target. The methods and technologies used are similar to those in Hit Discovery, but once the compound has shown activity in an animal model, it moves from 'hit' to 'lead.'

Increasing hit scrutiny

In this phase, we evaluate the target engagement or inhibition and biological activity using techniques such as fluorescence and mass-spectrometry inhibition assays, microcalorimetry-based binding assays, and bacterial and mammalian cell-toxicity assays. This provides us with an assessment of physicochemical properties, selectivity as well as an early ADME (absorption, distribution, metabolism, and excretion) profile in vitro. To further optimize the activity of the hits on their primary target we then apply iterative drug-design, synthesis and testing cycles. 

Moving hit to lead

Once a compound has sufficient activity in biochemical and cellular assays, we will test it in an animal model of the disease. If the compound shows activity in an animal, it becomes a lead. In the subsequent phase our goal is to optimize the lead by improving the pharmacokinetic properties and safety profile of a compound to identify a suitable drug candidate.
To achieve this, we make use of our advanced molecular pharmacology expertise and study and improve a hit compound’s mode of action towards a lead, e.g. through target-binding kinetics, allosteric modulation and functional selectivity of the compounds. This approach provides mechanistic insight into the compound-target interaction, which is important for the fields of pharmacology and toxicology and ultimately improves clinical success rates.

Understanding molecules through visualization

To be able to understand the mode-of-action of proteins and their interacting ligands at the molecular level, we have a large structural biology department. Here, we can apply various techniques such as X-ray crystallography, NMR and Cryo-Electron Microscopy (NeCeN).
To produce the proteins required for these studies we share a dedicated protein production facility together with the Leiden University Medical Center.

Case studies

Multiple Sclerosis, Parkinson’s and Alzheimer’s disease are the most common neurodegenerative disorders, but unfortunately no treatment that halts the disease exists. In recent years, lipid signaling in microglial cells has gained scientific attention for the development of novel therapies for these neuroinflammatory diseases. We are currently assessing lipase activity in human brain and preclinical models, and we have several hit- and lead optimization projects to modulate lipid signaling. Read more

Activity-based protein profiling (ABPP) allows the assessment of protein function in live cells and tissues). It is one of the pillars of chemical biology, and at LED3 we have taken it to the next level, and use it to accelerate drug discovery. Read more

Human cells are very complex. Different chemical processes are going on at the same time, but they are separated from each other because the cells are divided in compartments. These compartments can also hamper the effect of medicines. We have developed two imaging technologies that allow us to image the fate of intracellular pathogens in detail, so we can study how these antibiotics affect bacteria residing in different subcellular compartments. This may increase the success rate of new drug development. Read more

Since it was shown that many drugs are effective because they bind to their target for a long time, improving a compound’s target residence time could have great clinical value. We were the first to show the structure of CCR2, and that the protein can be inhibited from inside the cell by a small molecule. Read more

Cancer is the leading cause of death in the Netherlands, and, with over 100 different types of cancer, it’s not a simple disease. The discovery and development of new drugs has the ability to significantly improve the life span and quality of life for many cancer patients and their families. Therefore, we have many internal and external collaborations to pursue these new treatments. Read more

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