Guest Blogger: Darren Begley Hidden Pool Response

Folks, as you know (or may not) we have invited the reading community of Practical Fragments to guest blog. In response to this post we got this response from Darren.

If there's a hidden pool of FBDD talent, it is most likely in industry, not in academia. Fragment-based approaches are occasionally mentioned in courses or lectures by professors who want to appear up-to-date. But the only folks actually doing fragment-based work (as distinct from structure-based methods) are in a few key labs, all led by PIs with prior industry experience.

If you look at the 2008 FBLD Conference poster session, almost half of the presenters were from a single academic lab. The rest were largely virtual docking, traditional medicinal chemistry, or people from industry. One of the conference organizers told me that there were less than a handful of us graduate students in attendance; compare that to attendees at any given Gordon Conference. So I believe there are "puddles" of FBDD here and there, but not what I would call a vast resource.

That said, it seems the skills one needs to do FBDD can be acquired by other means in academia (ie. structural biology PhD, synthetic chemistry training, etc.). But if companies are looking to hire PhDs well-versed in fragment-based methodologies, there is currently not a huge group being freshly minted each year at commencement.

[Ed Note: I also think it is interesting that the industrial types that go to industry fair not well in terms of grants and such (my impression talking to the ones I know). But, I would be interested in hearing from those types also.]

Is FBDD a FADD?

Two reviews in the July issue of Drug Discovery Today provide an update on the state of FBDD.

The first, from researchers at the VU University, Amsterdam, and IOTA Pharmaceuticals, discusses 23 examples. Many of these have been reviewed elsewhere, but the paper also describes some studies that are unpublished or just reported at meetings. It’s a nice, thorough introduction to the field, and the organization of the review, by institution, gives a flavor of the diversity of approaches.

The second review, from researchers at Astex Therapeutics, provides a historical perspective and clinical focus. There are also useful tables of commercial suppliers of fragments as well as FBDD-derived compounds that have made it into clinical development.

In an accompanying editorial, Mark Whittaker of Evotec asks whether fragment-based drug discovery (FBDD) should really be called fragment-assisted drug discovery (FADD):

This is more than just a difference in semantics, but is, in fact, a broader question of when and how to apply fragment approaches to lead generation, either on their own or in concert with other hit finding techniques.

He goes on to explain that although fragment-based methods can be used by themselves to generate leads, they can also be complementary to other approaches to assess target druggability or focus later hit-finding. This conclusion is consistent with Practical Fragments’ latest poll, in which 85% of respondents reported that, far from being a fad, FBDD (or, if you like, FADD) is integrated in the hit finding stage at their company.

Fragments in Japan

We missed this meeting in our last events list, but Daisuke Tanaka of Dainippon Sumitomo Pharma reports on LinkedIn that:

On June 22, FBDD researchers from 11 Japanese pharmas/biotechs got together in hot and humid Tokyo. This one-day meeting, hosted by a crystallography-based CRO PharmAxess (www.pharmaxess.com) and an in silico-based CRO PharmaDesign (www.pharmadesign.co.jp/eng), started in the morning with reviews of benefits and techniques of FBDD, and then culminated in the afternoon with enthusiastic discussions on a non-confidential basis. The aim of this unofficial meeting was to share experienced problem-and-solution cases while carrying out FBDD, rather than reporting success stories in a conference fashion. Finally, it was adopted unanimously that the meeting should be held periodically once or twice a year.

Daisuke is organizing the next meeting – we’ll post the date and location as soon as we know (and everyone please contact us about other upcoming fragment events).

It’s great to see the field becoming more collaborative and international. Although the symposium proposals for Pacifichem 2010 are already set, perhaps a FBDD track at Pacifichem 2015 will give the fragment community an excuse to get together in Hawaii!

Fragments for sleeping sickness don’t lie still

In fragment-based drug discovery, the binding mode of the initial fragment often remains constant during the course of optimization (see AT9283 and AT7519 from Astex). But this isn't always true. An intriguing counterexample has recently been published in J. Med. Chem.

Ruth Brenk and colleagues at the University of Dundee were interested in pteridine reductase 1 (PTR1), an enzyme from Trypanosoma brucei, the protozoan that causes sleeping sickness. They used the program DOCK 3.5.54 (which has been successfully used for fragment-docking) to screen 26,084 commercially available fragments against the crystal structure of PTR1. After a variety of computational and manual filters were applied, the researchers purchased and tested 45 compounds in an enzymatic assay. Of these, 10 fragments inhibited PTR1 at least 30% at 100 micromolar concentration, the most potent of which was compound 4 (below).



Removing the chlorine atom to generate compound 5 resulted in a dramatic loss in activity, while adding the dichlorobenzyl moiety caused a similarly large boost in activity (compound 9). The researchers were able to characterize the binding mode of each of these molecules crystallographically, and it turns out that, despite sharing a common aminobenzimidazole core, they all bind in very different fashions.

The initial compound 4 binds in two orientations, one of which closely resembles the binding mode predicted from the computational screen, with hydrogen bonds between the fragment and the enzyme cofactor NADP+. Compound 5 makes indirect (water-mediated) hydrogen bonds with the cofactor, while compound 9 binds in a completely different manner some distance from the cofactor.

Brenk and colleagues observed a hydrophobic pocket near compound 9 which they exploited to generate the low nanomolar compound 12; crystallography confirmed this binds in a similar fashion to compound 9. This molecule also displayed impressive selectivity against the potential off-target dihydrofolate reductase. Unfortunately, despite the promising biochemical activity of compound 12, it displays only modest activity against T. brucei in cell culture.

This study illustrates two important points. First, it can be hazardous to assume that even very closely related molecules, such as 4 and 5, bind in the same manner. Second, because of this, one should not adhere too slavishly to models, even those based on crystal structures. The binding modes of compounds 4 and 5 would not accommodate the dichlorobenzyl moiety, and yet this addition provided a sizable boost in potency. Sometimes it pays to make substitutions even where you wouldn’t expect them to make sense, especially where the changes are easy to make.