18 November 2013

Natural products as fragments

Natural products were used as drugs long before there was a drug industry, and there is a case to be made that they make good starting points for lead discovery. For one thing, they tend to be more “three-dimensional” than many synthetic molecules. For another, the fact that some organism, somewhere, made them proves that they can bind to proteins. Practical Fragments has previously highlighted examples in which natural products were conceptually fragmented into smaller molecules or incorporated into a fragment library. In a new paper in ACS Chemical Biology, Ronald Quinn at Griffith University and a team of Australian and US collaborators describe a fragment library consisting entirely of natural products.

The researchers assembled a library of 331 natural products with the following characteristics:

  • MW ≤ 250 Da (mean = 195.6)
  • ClogP < 4 (mean 0.4)
  • hydrogen bond donors ≤ 4 (mean 1.3)
  • hydrogen bond acceptors ≤ 5 (mean 2.6)
  • rotatable bonds ≤ 6 (mean 2.2)
  • polar surface area ≤ 45% (mean 17.7%)

The maximum number of donors and acceptors allowed is slightly higher than typical in a fragment library, consistent with the fact that natural products tend to have more oxygen and nitrogen atoms than your typical Suzuki-derived biphenyl. However, the molecular weights are kept low, and despite the tolerance for more lipophilic molecules, the vast majority of the library has ClogP < 3 (with many molecules having ClogP < 0).

Having assembled the library, the researchers used native mass spectrometry to screen pools of eight fragments against the malarial enzyme Plasmodium falciparum 2′-deoxyuridine 5′-triphosphate nucleotidohydrolase (PfdUTPase). They found that a molecule called securinine binds to the enzyme, and six analogs also showed varying degrees of binding as assessed by mass spectrometry.

At this point things get a bit strange. Most of the molecules show some anti-plasmodial activity in culture, but they all seem to modestly activate PfdUTPase. It is unclear whether these two observations are mechanistically related: is the activation of PfdUTPase really what’s causing the anti-plasmodial activity, or are the molecules hitting a different target?

In fact, securinine comes up as a hit in a variety of different biological assays. Looking at the molecular structure this is perhaps not surprising: it contains a reactive electrophilic center that has previously been shown to react with amines under mild conditions, so presumably it can react with all sorts of biological nucleophiles in vivo. This is not to say that covalent inhibitors are unacceptable – dimethyl fumarate looks set to become a blockbuster drug – but it is nice to know if you are dealing with them, and the authors seem not to have considered the possibility.

In the end, I do think libraries of natural products such as these could be useful, but they will require care in their construction, use, and interpretation. Just as there are many synthetic compounds best left out of screening collections, the same goes for natural products. Toxoflavin, for example, is a notorious redox cycling PAIN that has (embarrassingly) been reported as an inhibitor for multiple targets with no evidence for specificity. I’m not ready to put securinine into this category, but I would urge caution.

Just because something is natural doesn’t mean it’s healthy.


Dr. Teddy Z said...

Interesting take on NP. My belief (which is likely wrong) is part of the problem with NP is that the chemistry is REALLY tough and thus doing SAR on them is almost impossible. So, outside of the rare cases where there are some easily available related compounds, where does this lead you?

Chris said...

I have not seen the structures of the rest of the natural product fragment library, but I guess many are relatively simple structures? If so the chemistry should be more traceable.

Dr. Teddy Z said...

Mebbe, but the one hit they showed has plenty of chirality and bridging carbons.

Brandon Findlay said...

There's quite a few natural products that have become drugs without any modification at all, or are derived from isolated NPs (ex. a fair chunk of our antibiotics).

An SAR screen is always welcome, but not always mandatory.

Dan Erlanson said...

SAR can indeed be challenging with natural products. However, since many of them have been the object of chemical manipulation for decades there is often a rich literature on analoging. Securinine itself, for example, can be readily aminated enantioselectively. That said, more fundamental changes in the skeleton are not necessarily trivial; a 2009 total synthesis of securinine is 10 steps, though with a relatively high (20%) overall yield.

Anonymous said...

Although bound by pace and the unforgiving laws of economic patience, this is a very exciting approach. To Dr. Teddy, sure the SAR is harder -- hire some chemists -- but as with all natural products the potential advantage is that the bio-availability issues have been prescreened by the laws of natural selection.

Michael S Chimenti said...

Please excuse my ignorance, but how far does the NP have to be modified during the SAR process to become novel IP that may be patent-protected (and thus, profitable)?

Does this impact the utility of fragment NP libraries vs synthetic fragment libraries?