Essays in Biochemistry special issue: Structure-based drug design

Structure-based drug design is often an integral part of fragment-based drug discovery. Indeed, a majority of respondents in a recent poll would not work on a fragment without experimental structural information. Given the close relationship between SBDD and FBDD, I was pleased to learn that a recent issue of Essays in Biochemistry is completely devoted to SBDD.

The collection begins with an editorial by issue editors Rob van Montfort and Paul Workman, both at the Institute of Cancer Research. It briefly introduces SBDD and FBDD and provides an overview of the rest of the issue. It also contains a laudable call for rigor, awareness of artifacts, and making data publicly available.

The first full review, by Martin Noble and collaborators at Newcastle University, discusses the role of SBDD in discovering inhibitors of cyclin-dependent protein kinases (CDKs), with a particular focus on selectivity. Several small molecules are discussed, though I do wish the paper included the fragment-derived compound AT7519, which made it to phase 2 clinical trials.

The following paper, by Bas Lamoree and Rod Hubbard (University of York), is completely devoted to FBLD. This is a concise and self-contained review of the field, and is also sufficiently up to date that it provides a good primer on the state of the art.

Chris Abell and collaborators at the University of Cambridge discuss mass spectrometry for fragment screening in the next paper, including ultrafiltration, WAC, HDX-MS, and native mass spectrometry (though not Tethering). The review also includes a handy table summarizing the advantages and limitations of commonly used fragment-finding methods.

Next up is another review devoted to FBDD, this one from Benjamin Cons and his Astex colleagues. The focus is on challenging drug targets such as BCL-family proteins and KEAP1 where SBDD was pivotal, and the researchers particularly emphasize the utility of X-ray crystallography.

NMR was the first experimental technique used for FBDD, and this is the topic of a paper by Gregg Siegal and colleagues at ZoBio. The review includes examples where NMR revealed that crystallographically-determined binding sites were not biologically relevant. Newer techniques, such as NMR², are also discussed.

Frank von Delft and collaborators describe the fourth funding phase of the Structural Genomics Consortium (SGC), which includes generating a couple dozen “target enabling packages” around new genetic targets. The ten year goals are certainly ambitious: “no crystal structure is complete without a careful analysis of the target’s disease linkage, a fully analysed fragment screen, and a series of follow-up compounds with demonstrated potency and rationalized SAR.” Given the tools and partnerships they have already established, I wouldn’t bet against them.

Hitting a single protein target can be difficult enough, but Scott Hughes and Alessio Ciulli (University of Dundee) focus on ternary interactions, in which a small molecule acts as a “molecular glue” to bring proteins together. PROTACS, molecules designed to target proteins for degradation, comprise one class that has garnered significant attention recently, and as we’ve noted previously FBDD could play a role in discovering and optimizing them. Targeted protein degradation is also the subject of the next paper, by Honorine Lebraud and Tom Heightman (Astex). In particular, the researchers focus on the use of click chemistry to rapidly build chemical probes that degrade specific target proteins.

Crystallographers have steadily been shrinking how big a crystal must be for analysis, in part due to brighter X-ray beams. Michael Hennig and collaborators at leadXpro discuss X-ray free electron lasers, which were experimentally realized less than a decade ago. The energy of these photons is more than a billion times higher than in the newest synchrotrons – so powerful that they destroy the crystals almost instantaneously, but not before producing a diffraction pattern. This means that tens of thousands of individual crystals need to be studied in order to obtain a full dataset. Needless to say the technical and computational demands are intense and still being optimized. The rewards include being able to use weakly-diffracting microcrystals, such as those of membrane proteins, and the ability to collect data at physiological temperatures, as opposed to the cryogenic temperatures typically used.

The last paper, by David Barford and collaborators at the MRC Laboratory, discusses the use of cryo-electron microscopy – which was recognized by a Nobel Prize this year. Single particle cryo-EM does not require a crystal at all, and recent advances have made near-atomic resolution possible. The idea is to image thousands of individual proteins and then computationally reconstruct them. The review discusses multiple protein-ligand complexes, and although none of these are from fragment programs, some of the ligands are approaching the size of fragments.

This collection of papers nicely captures where SBDD currently stands and illuminates the path ahead. For at least a while all the articles are free to download – so check them out now!