The Chemical Probe Facility is part of the Leiden Early Drug Discovery & Development (LED3) center. Activity-based protein profiling (ABPP) is one of the pillars of chemical biology. ABPP determines the activity of entire protein families in living cells and tissues under physiological conditions, such as in the presence of protein interaction partners, post-translational modifications, endogenous substrates and cofactors.

In addition, ABPP shows how protein activity is modulated by hits, leads and experimental drugs. This makes it a powerful tool in medicinal chemistry and a driving force in accelerating the discovery of drugs by selecting the right compounds at an early stage. ABPP also enables visualization of target proteins in cells and tissues, thereby providing an essential correlation between target binding and functional readout in cellular and ultimately animal models. Underlying technologies for efficient identification of new druggable targets are available. To date, we have compiled the most comprehensive (and constantly growing) activity-based chemical probe collection worldwide, including probes selective for serine hydroxases, cysteine proteases, threonine proteases, glycosidases, ligases, lipases, amidases and kinases, as well as for nine different amino acids. The Chemical Probe Facility includes an N-STORM super resolution confocal microscope (Nikon Eclipse Ti2-E), SYNAPT G2 IMS, an MALDI-TOF MSI, a nanoLC ESI system (Waters); LCQ-Advantage Max LC-MS system (Thermo Fisher) and a Q-Exactive Orbitrap.

The second pillar of the facility is the development of assays for new molecular pharmacological concepts, such as prolonged drug-target binding kinetics, covalent interaction or allosteric modulation. One advantage of these new concepts is that they result in molecules with so-called "insurmountable antagonism", which has great potential for cancer therapies. So-called PROTACs, which induce degradation  of  targets, also fall into the category. These types of substances represent a revolution in the research of new medicines. Finally, compounds may stabilize various protein conformations, thereby inducing differential activation of intracellular signaling pathways, also known as biased signaling. Depending on which cellular signal transduction route is triggered, this may lead to more effective and/or safer candidate drugs. The ultimate goal is therefore to give molecules a better pharmacological profile before they enter the clinical phase.

A third pillar of the Chemical Probe Facility is the application of artificial intelligence for the design and synthesis of chemical probes and small molecules. Finding and optimizing candidate drugs is done against a background of 10³³  to 10⁶⁰  possible drug-like molecules. Searching this 'chemical space' can be significantly improved and accelerated by the use of artificial intelligence (AI). Molecule generators developed in Leiden based on reinforcement learning proposes new ligands with predicted affinity and selectivity. By incorporating the latest AI-based retrosynthesis algorithms, the synthesizability of the molecules generated in silico can already be taken into account in the design process. By using AI in the design phase, the hit-to-lead and lead-to-candidate optimization can be improved by directly considering multiple design goals such as affinity, selectivity and synthesization. This reduces the number of optimization cycles required, which ultimately increases throughput and reduces costs. Leiden has a high-performance computing facility dedicated entirely to  computational drug development and AI. In addition, active collaborations with the Leiden Institute of Advanced Computer Science (LIACS) ensure that breakthroughs in fundamental AI development are quickly incorporated into drug research.