Universiteit Leiden

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Division of Drug Discovery & Safety

Medicinal Chemistry

The mission in this research group, headed by Ad IJzerman, is to design and synthesize novel and better ligands for drug targets. Drug discovery is a lengthy but inspiring adventure. It is often an interplay between academic institutes and pharmaceutical industry, in which scientists at university develop novel concepts that are further exploited by their colleagues in pharmaceutical companies. Our group has established a strong position in this collaborative effort by focusing on a selected set of drug targets, in particular so-called G protein-coupled receptors (GPCRs). These receptors bind many of today’s medicines. Still, these “established” targets have not yet revealed their full characteristics, and that’s precisely what we focus on. Can we unravel the mysteries of these targets and use our discoveries for developing novel concepts for drug discovery?

Ad IJzerman and international colleagues have written many reviews on GPCR ligands (among others in Pharmacological Reviews), some of which have become citation classics. In the following seminar Ad discusses his views on this fascinating branch of science: ‘Breaking and making: the art of medicinal chemistry’. Pivotal to this work is information on ligands used as pharmacological tool compounds. Despite the sheer endless synthetic efforts, such ligands may not be that excellent in terms of affinity and/or selectivity for, e.g., human receptors. Moreover, the binding kinetics of such ligands have rarely been characterized, let alone of being used for lead optimization. Also, the concept that ligands may occupy distinct sites on receptors (orthosteric vs allosteric binding) has not been fully explored.

Fortunately, over the last decade more and more 3D structures of GPCRs have become available, a number of which we have contributed to ourselves. The structures provide a detailed insight in where and how ligands bind to their receptors, which amino acids are involved in the interaction with (moieties of) the ligands, and how varied the interaction can be and even occur at multiple sites on the receptor. This structural biology component complements the pharmacological findings, enabling the firm foundation of novel concepts of interaction.

An illustration of this reasoning is the structure elucidation of the chemokine CCR2 receptor. We learned that for the actual crystallization of the protein to occur two ligands needed to bind simultaneously. If not, the protein structure was too fragile to survive the conditions of crystallization. Interestingly, it appeared that the two ligands bound to very different sites on the receptor and that these sites influenced each other. The binding of one ligand (BMS681) increased the binding of the other (CCR2-RA-[R]), an illustrative example of allosteric modulation. At the same time each of the two ligands blocked the action of the endogenous chemokine ligand normally binding to the receptor. However, BMS681 binds to the site where the chemokine interacts with the receptor as well, leading to a competitive interaction. This is not always effective, as in severe disease such as rheumatoid arthritis the amounts of chemokine are so high that ligands such as BMS681 cannot productively compete. The other compound, CCR2-RA-[R], binds at a very distant location, close to the intracellular environment. Since it is close to the site where the G protein binds, the latter cannot interact very well with the receptor, leading to a receptor blockade that is non-competitive/allosteric in nature.

This is just one example of the avenues one can go to obtain ‘better ligands’. More generally speaking: in this research line we have set ourselves the goal of synthesizing tailored compounds for the drug targets in our research programs, along four lines depending on the target’s ‘need’, i.e. i) affinity, ii) selectivity, iii) binding kinetics and iv) allosterism. These four themes are briefly described on the next pages.

Key publications