Description
In these lectures, I will introduce the basic concepts and possibilities of protein structure-based drug design (SBDD). A prototypical approach in this area is docking. Docking and related methods are based on force fields, describing molecular interactions with biophysical or empirical terms. In the absence of an experimentally determined protein structure, such force fields can also be used to calculate 3D structures through homology modeling. The combination of all techniques constitutes a powerful tool set that can be employed to search for ligands with tailored properties.
I will also highlight key lessons learned from docking multi-million compound libraries to different G protein-coupled receptors (GPCRs), the protein family most frequently targeted by present-day drugs. The most prominent example is the first unbiased screen we did with the β2-adrenergic receptor, which produced six novel binders – some of them with chemotypes previously undescribed for this target – and a most potent compound with an affinity of 9 nM [1]. Further examples include the chemokine receptors CXCR3 and CXCR4, where we identified potent ligands with tailored selectivity profiles with high hit rates [2]. The malleability of GPCRs seems to make multi-conformation screenings a good strategy, as we have shown for the A1 subtype of the adenosine receptors [3]. At the low-throughput end, I will talk about the docking-based in-depth analysis of four ligands of the orexin receptor subtype 2 [4]. The challenge in this system were the unusual binding mode of the crystallographic ligand as well as the comparative scarcity of binding site features. These learnings have now been translated into additional ligands of this highly investigated system.
References
[1] Kolb P, Rosenbaum DM, Irwin JJ, Fung JJ, Kobilka BK, et al. Structure-based discovery of β2-adrenergic receptor ligands. Proc. Natl. Acad. Sci. U. S. A. 106 (2009), 6843–6848.
[2] Schmidt D, Bernat V, Brox R, Tschammer N, and Kolb P. Identifying modulators of CXC receptors 3 and 4 with tailored selectivity using multi-target docking. ACS Chem. Biol. 10 (2015), 715–724.
[3] Kolb P, Phan K, Gao ZG, Marko AC, Sˇali A, et al. Limits of ligand selectivity from docking to models: In silico screening for A1 adenosine receptor antagonists. PLoS ONE 7 (2012), e49 910.
[4] Yin J, Mobarec JC, Kolb P, and Rosenbaum DM. Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant. Nature 519 (2015), 247–250.
