I have been lucky to work on a lot of systems that very much interest me. I, in particular, love metallo-proteins. I worked on rubredoxin as a post-doc and when I moved into industry I worked on a slew of metalloproteins. So, I love it now when I see papers on targets I used to work on. This paper does exactly that while also letting me riff (later) on Natural-Product-Derived Fragments (NPDF).
NPDF has a long history in FBDD having been discussed here, here, here, and so on. Many vendors and some companies have NPDF libraries (whether they call them that or not). However, these libraries have yet to be proven to be an efficient route for "discovering clinical drug candidates". Lanz and Riedl set out to do this against MMP-13 (how many of your just said, yeah I worked on that target?). All MMP-13 clinical candidates with strong ZBG (Zinc-binding groups) have failed. They are aiming to develop a MMP-13 without a strong ZBG. Of course, we have seen a LOT of work towards this goal: here, here, and here for example. The authors propose that the use of NPDF prevents the problem of using fragments with "debatable biological properties". This seems to the be the argument used by the NPDF people, since these fragments are found in nature they have desirable properties. I have never bought this line of reasoning for a variety of reasons.
To their end, the authors selected uracil as their starting NPDF for these reasons: good synthetic starting points, cis amide bonds, and its found in a variety of natural products (nucleic acids). They docked it in the S1' non-zinc binding site and found a strongly conserved binding site. [For me, and I would imagine a whole lot of people, this fits in the "things you already knew" category.] The uracil interacted with the NH an CO of Met232 via its cis amide bonds and "addresses" Lys228. Several compounds were made from the uracil starting point (Figure 1):
|Figure 1. 2: 5 uM vs. MMP-13, < 50% Inhib against 1,2,3,7,8,9,12, and 14 at 20 uM. 3: 10 nM vs. MMP-13, < 50% Inhib against 1,2,3,7,8,9,12, and 14 at 20 uM2: 5 nM vs. MMP-13, < 50% Inhib against 1,2,3,7,8,9,12, and 14 at 10 uM|
So, in the end, they have created a potent and selective compound. They did use a NPDF as a starting point. Making these compounds is not something that bowls me over either for a Technical Difficulty score or Artistic Merit. However, I would not go so far as to say that they have validated the NPDF approach. I think to show that a generic approach works you need more than one (relatively well known) target with more than one (relatively well known) fragment.