It seems the fragment calendar was front-loaded this year, but there are still a few upcoming events.
June 8-9: GTCbio is holding its “Fourth Assay Development and Screening Technologies” conference in San Francisco, and there is one session on fragment-based screening. (Full disclosure: I’ll be speaking at that one - stop by and introduce yourself!)
June 26: Select Biosciences has a “Fragment-Based Lead Discovery Summit” in London. It’s only one day, but there are a number of great speakers.
September 21-23: Last but much-anticipated, FBLD 2009 will be held in York, UK.
Regarding previous events, RSC’s Fragments 2009 has been covered both here as well as on FBDD-Lit. There is also an excellent eBriefing of the NYAS symposium on molecular diversity that can be found here.
As always, let us know if we’ve missed anything and we’ll get the word out.
18 April 2009
10 April 2009
LELP fragments reach their potential
In last month’s issue of Nature Reviews Drug Discovery, György Keserü of Gedeon Richter and Gergely Makara of Merck published a thought-provoking analysis of recent trends in lead discovery. Their results illustrate the potential of fragment-based methods, but also point out the still sizable gap from current practice.
The authors assembled a database of 335 hit-lead pairs derived from high-throughput screening (HTS) that were published between 2000 and 2007. They also assembled a database of 84 non-HTS hit-lead pairs published between 2000 and February 2008, consisting of fragment-based, virtual screening, natural product, and miscellaneous examples. They then compared properties – such as potency, molecular mass, logP, logS (a calculated measure of solubility), and ligand efficiency – of the initial hits with the resulting leads.
The results for HTS hits are not pretty: the lipophilicity as assessed by logP was considerably higher on average for HTS hits than for hits from any other methods, and this only increased as the hits were progressed to leads. The same goes for (in)solubility (as measured by logS). Even more alarming, the average properties of even the hits are worse than those of a collection of 541 approved drugs.
Fragment hits start out with the lowest lipophilicity and highest predicted solubility, but during hit-to-lead optimization these properties deteriorate to the point where they are similar on average to leads derived from HTS. Also surprisingly, the ligand efficiency of fragment hits and leads are, if anything, lower than their HTS counterparts, contrary to expectations. Even the average molecular weight of fragment-derived leads is not much lower than HTS-derived leads.
So what’s going wrong? The authors point out that, at most larger companies, fragment-based approaches are often only attempted after HTS has failed, suggesting that the targets tackled by fragment-based methods may be inherently more difficult. But they also suggest that in the early stages of hit-to-lead optimization the primary measure of success is how many compounds are delivered to lead optimization, which could encourage rapid hit expansion with simple chemistries to rapidly boost potency by adding grease, leading to more hydrophobic, less soluble molecules that will ultimately struggle in the clinic.
The authors suggest a new metric, ligand-efficiency-dependent lipophilicity, or LELP, to help avoid this trap:
LELP = (log P / LE)
Since a desirable logP range is between 0 and 3, and a desirable ligand efficiency is above 0.4, one should strive for LELP values between 0 and 7.5. There are already lots of metrics out there for evaluating molecules: see, for example, discussions of %LE, antibacterial efficiency, and fit quality (also here and here). Is a new one really necessary? Perhaps, if it gets people to focus on non-lipophilic means of increasing potency.
The authors end on a positive note for fragments:
Bearing in mind the sampling of chemical space, hit properties and synthetic accessibility, we consider that fragment hits are the optimum starting points for lead discovery and optimization.
There is, however, a burden on the team transforming a fragment hit into a viable lead: it is important to focus not merely on improving potency, but on maintaining as many of the fragment-like properties that make fragments attractive starting points in the first place. Although this goes without saying, analyses like this one suggest that it still needs to be said – and heard.
The authors assembled a database of 335 hit-lead pairs derived from high-throughput screening (HTS) that were published between 2000 and 2007. They also assembled a database of 84 non-HTS hit-lead pairs published between 2000 and February 2008, consisting of fragment-based, virtual screening, natural product, and miscellaneous examples. They then compared properties – such as potency, molecular mass, logP, logS (a calculated measure of solubility), and ligand efficiency – of the initial hits with the resulting leads.
The results for HTS hits are not pretty: the lipophilicity as assessed by logP was considerably higher on average for HTS hits than for hits from any other methods, and this only increased as the hits were progressed to leads. The same goes for (in)solubility (as measured by logS). Even more alarming, the average properties of even the hits are worse than those of a collection of 541 approved drugs.
Fragment hits start out with the lowest lipophilicity and highest predicted solubility, but during hit-to-lead optimization these properties deteriorate to the point where they are similar on average to leads derived from HTS. Also surprisingly, the ligand efficiency of fragment hits and leads are, if anything, lower than their HTS counterparts, contrary to expectations. Even the average molecular weight of fragment-derived leads is not much lower than HTS-derived leads.
So what’s going wrong? The authors point out that, at most larger companies, fragment-based approaches are often only attempted after HTS has failed, suggesting that the targets tackled by fragment-based methods may be inherently more difficult. But they also suggest that in the early stages of hit-to-lead optimization the primary measure of success is how many compounds are delivered to lead optimization, which could encourage rapid hit expansion with simple chemistries to rapidly boost potency by adding grease, leading to more hydrophobic, less soluble molecules that will ultimately struggle in the clinic.
The authors suggest a new metric, ligand-efficiency-dependent lipophilicity, or LELP, to help avoid this trap:
LELP = (log P / LE)
Since a desirable logP range is between 0 and 3, and a desirable ligand efficiency is above 0.4, one should strive for LELP values between 0 and 7.5. There are already lots of metrics out there for evaluating molecules: see, for example, discussions of %LE, antibacterial efficiency, and fit quality (also here and here). Is a new one really necessary? Perhaps, if it gets people to focus on non-lipophilic means of increasing potency.
The authors end on a positive note for fragments:
Bearing in mind the sampling of chemical space, hit properties and synthetic accessibility, we consider that fragment hits are the optimum starting points for lead discovery and optimization.
There is, however, a burden on the team transforming a fragment hit into a viable lead: it is important to focus not merely on improving potency, but on maintaining as many of the fragment-like properties that make fragments attractive starting points in the first place. Although this goes without saying, analyses like this one suggest that it still needs to be said – and heard.
07 April 2009
Book Review on FBDD Book
There is a review just publish ASAP in JACS of the Zartler and Shapiro edited book on FBDD. Overall, it is a nice review (Thanks to Andrew and Phil). There is one error (chapters 4-11 are EIGHT chapters, not seven) and one critique that I want to address.
Although there is a paragraph in Chapter 3 covering X-ray methods, which are mentioned in the introductory chapters, it would have been nice to have an entire chapter dedicated to these methods as several groups in industry have applied them successfully.
Mike and I made a conscious choice NOT to include any chapters on X-ray. We thought that of all the methods for FBDD X-ray has been done; there was nothing new to the field that our book could contribute. The focus of this book was on practical applications and newer techniques. There are a plethora of nice reviews out there, X-ray focused companies, and three chapters entirely or mostly about using X-ray in the Jahnke and Erlanson book.
What are the feelings of others? Did we swing and miss by leaving that topic out of the book or is X-ray the "mature" FBDD method? I would argue (and did in my editorial choice) that there is little left to say about X-ray that hasn't already been said.
[Update]: Zartler and Shapiro:Amazon.com Sales Rank: #1,595,845 in Books.
Jahnke and Erlanson: Amazon.com Sales Rank: #1,238,437 in Books
02 April 2009
Nuclear Magnetic Crystallography part II
In what can only be seens as a cosmic convergence, a second paper has appeared on NMR-X-ray hybridization. This one is a collaboration from Medivir, The University of Florence, and Bruker Biospin. This method is aimed at generating structural information for a family of related proteins (in this case MMPs). The authors argue that the cost of 13C and 15N labeling is so low that such samples should be readily available, making this method widely applicable. The thrust of their method is the use of X-filtered NOESY spectroscopy to generate distance constraints, then use Autodock to determine binding. I expect that this will get covered on our FriendBlog, the FBDD-Lit Blog, so I won't go into many details.
Instead I would like to make this a discussion of the perceived value of methods such as this to the FBDD community. I, despite being an NMR jock by trade, don't feel that labeled protein methods, give enough bang for the buck, compared to ligand-based methods. Will methods such as described Isaksson et al. change that cost-benefit analysis?
What do other people think about the value and the proper role of NMR?
Instead I would like to make this a discussion of the perceived value of methods such as this to the FBDD community. I, despite being an NMR jock by trade, don't feel that labeled protein methods, give enough bang for the buck, compared to ligand-based methods. Will methods such as described Isaksson et al. change that cost-benefit analysis?
What do other people think about the value and the proper role of NMR?
01 April 2009
Nuclear Magnetic Crystallography
There is often a competition, explicit or implied, between NMR spectrometrists and X-ray crystallographers. A new technique merges the best of both worlds
Researchers at the University of Shutka, Russia, have constructed a unique NMR spectrometer with a hole bored all the way through the magnet and probe, perpendicular to the main sample cavity. This hole allows the researchers to send an X-ray beam directly into a crystal mounted in a specially designed sample chamber, allowing them to screen for compound binding by NMR while simultaneously obtaining crystal structures. Of course, due to the solid state (crystalline) form of the protein, the researchers can’t actually detect the protein itself by NMR, but by mounting the crystal in a flow cell and testing pools of fragments, they can use target-based NMR to determine which fragments bind to the protein. Once they find a fragment that binds, they can then immediately obtain the crystal structure. The researchers are planning to bring their NMR to a synchrotron to have access to a brighter X-ray source.
Will the technique become widely accepted? If so, this could be the start of a beautiful friendship.
Researchers at the University of Shutka, Russia, have constructed a unique NMR spectrometer with a hole bored all the way through the magnet and probe, perpendicular to the main sample cavity. This hole allows the researchers to send an X-ray beam directly into a crystal mounted in a specially designed sample chamber, allowing them to screen for compound binding by NMR while simultaneously obtaining crystal structures. Of course, due to the solid state (crystalline) form of the protein, the researchers can’t actually detect the protein itself by NMR, but by mounting the crystal in a flow cell and testing pools of fragments, they can use target-based NMR to determine which fragments bind to the protein. Once they find a fragment that binds, they can then immediately obtain the crystal structure. The researchers are planning to bring their NMR to a synchrotron to have access to a brighter X-ray source.
Will the technique become widely accepted? If so, this could be the start of a beautiful friendship.
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