We’re in the last quarter of 2009, and I know of just one more event this year involving fragments:
October 13: The Life Science Regional Technology Symposium will be held in Somerset, NJ, and Dr. Teddy Z. will be one of several excellent speakers.
2010
Next year is starting to take shape nicely, and two events have put out calls for abstracts, so if you have something interesting to present, now’s your chance!
February 3-5: Cambridge Healthtech Institute’s 17th International Molecular Medicine Tri-Conference will be held in my beautiful city of San Francisco, with a track on medicinal chemistry that will have some fragment talks, and a short course on “Fragment-Inspired Medicinal Chemistry” on February 2.
March 21-25: The spring ACS meeting will also be held in San Francisco. There will be a symposium on “Fragment Based Drug Design: Novel Approaches and Success Stories,” and Rachelle Bienstock at the FBDD LinkedIn site has put out a call for abstracts, due October 19.
April 20-25: The Keystone Symposium on computer-aided drug design will take place in brisk Whistler, British Columbia. Although not exclusively devoted to fragments, the schedule shows several talks on the topic.
April 27-28: Cambridge Healthtech Institute’s Fifth Annual Fragment-Based Drug Discovery will be held in summery San Diego. This conference has also put out a call for speakers, with a deadline of October 16.
Know of anything else? Organizing a fragment event? Let us know and we’ll get the word out.
Showing posts with label 2009. Show all posts
Showing posts with label 2009. Show all posts
27 September 2009
FBLD 2009
Fragment-based Lead Discovery Conference 2009 just concluded in York, UK; it was the second in what will hopefully be a continuing series. With more than two dozen talks and as many posters spread over three days, most of them very high quality, it is impossible to summarize even the highlights (and I don’t want to scoop pending publications). Instead I’ll just jot down a few impressions.
On the broad topic of why FBLD is useful, an interesting shift in emphasis seems to have occurred. A few years ago a key argument in favor of fragments was getting compounds to the clinic faster, but there is now a greater focus on quality over speed. In summarizing over a decade of fragment work at Abbott, Phil Hajduk noted that FBLD hits consistently bind more efficiently than those from HTS. Similarly, Chris Murray of Astex noted that, among their five clinical candidates (four of which target kinases), the average ClogP was 1.7 (vs 4.1 for a set of 45 reported orally active kinase inhibitors), while the average molecular weight was 390 (vs 457).
One theme that differentiated this meeting from others was a strong focus on modeling: an entire day was devoted to sessions on “fragments, scoring functions and docking” and “design from fragments.” This concluded with a lively round table discussion, chaired by Vernalis’ James Davidson, titled “Chemistry challenging modeling.” But challenges didn’t only come from chemists: one prominent modeler noted that there have been no fundamentally new approaches to modeling in the past two decades; another asked why, despite the number of interesting new chemistries out there, so many modelers restrict themselves to the same old standbys such as amide bonds.
Part of the problem with modeling, of course, is separating hits from noise: true hits often show up near – but not at – the top of a ranked list, so how does one decide what is worth pursuing? Phil Hajduk discussed the use of “Belief Theory”, in which the similarity of an unknown molecule to a known active is used to evaluate the unknown.
Another problem is the quality of primary data: As Hajduk noted, “no one takes experimental error into account” when predicting ligand binding, and a recent analysis suggests that over-fitting data is a substantial problem with many computational approaches. This is all the more problematic when the data are not just noisy but spurious; Practical Fragments has noted the problem of aggregation, and UCSF’s Brian Shoichet emphasized this point, noting that 85-95% of hits from a high-throughput screen could be artifacts, while 85-100% of what remains could also be bogus. He did note, though, that fragments are less problematic in this regard than larger molecules. And Genentech’s Tony Giannetti, Vernalis’ James Murray, and others illustrated how surface plasmon resonance is effective at weeding out bad actors.
Getting better data will clearly be essential to getting better models, but one essential category, the forces involved in protein-small molecule interactions, is still poorly understood. Gerhard Klebe of the University of Marburg presented a detailed and elegant set of experiments exploring the effects of chemical structure on the enthalpy and entropy of binding to the protein thrombin. He emphasized that desolvation of fragments from water is critical, and only possible if compensated by strong interactions with the protein. This also implies that you want fragments that have low desolvation penalties as well as high solubilities – a tricky balancing act.
FBLD 2009 was held barely six months after Fragments 2009, and it is a testament to the vibrancy of the field that both conferences managed to be so successful and exciting while sharing very few speakers in common.
For the other two hundred plus attendees at the conference, what were some of your impressions?
On the broad topic of why FBLD is useful, an interesting shift in emphasis seems to have occurred. A few years ago a key argument in favor of fragments was getting compounds to the clinic faster, but there is now a greater focus on quality over speed. In summarizing over a decade of fragment work at Abbott, Phil Hajduk noted that FBLD hits consistently bind more efficiently than those from HTS. Similarly, Chris Murray of Astex noted that, among their five clinical candidates (four of which target kinases), the average ClogP was 1.7 (vs 4.1 for a set of 45 reported orally active kinase inhibitors), while the average molecular weight was 390 (vs 457).
One theme that differentiated this meeting from others was a strong focus on modeling: an entire day was devoted to sessions on “fragments, scoring functions and docking” and “design from fragments.” This concluded with a lively round table discussion, chaired by Vernalis’ James Davidson, titled “Chemistry challenging modeling.” But challenges didn’t only come from chemists: one prominent modeler noted that there have been no fundamentally new approaches to modeling in the past two decades; another asked why, despite the number of interesting new chemistries out there, so many modelers restrict themselves to the same old standbys such as amide bonds.
Part of the problem with modeling, of course, is separating hits from noise: true hits often show up near – but not at – the top of a ranked list, so how does one decide what is worth pursuing? Phil Hajduk discussed the use of “Belief Theory”, in which the similarity of an unknown molecule to a known active is used to evaluate the unknown.
Another problem is the quality of primary data: As Hajduk noted, “no one takes experimental error into account” when predicting ligand binding, and a recent analysis suggests that over-fitting data is a substantial problem with many computational approaches. This is all the more problematic when the data are not just noisy but spurious; Practical Fragments has noted the problem of aggregation, and UCSF’s Brian Shoichet emphasized this point, noting that 85-95% of hits from a high-throughput screen could be artifacts, while 85-100% of what remains could also be bogus. He did note, though, that fragments are less problematic in this regard than larger molecules. And Genentech’s Tony Giannetti, Vernalis’ James Murray, and others illustrated how surface plasmon resonance is effective at weeding out bad actors.
Getting better data will clearly be essential to getting better models, but one essential category, the forces involved in protein-small molecule interactions, is still poorly understood. Gerhard Klebe of the University of Marburg presented a detailed and elegant set of experiments exploring the effects of chemical structure on the enthalpy and entropy of binding to the protein thrombin. He emphasized that desolvation of fragments from water is critical, and only possible if compensated by strong interactions with the protein. This also implies that you want fragments that have low desolvation penalties as well as high solubilities – a tricky balancing act.
FBLD 2009 was held barely six months after Fragments 2009, and it is a testament to the vibrancy of the field that both conferences managed to be so successful and exciting while sharing very few speakers in common.
For the other two hundred plus attendees at the conference, what were some of your impressions?
06 August 2009
Fragment-based conferences in 2009 and 2010
Hard to believe, but 2009 is more than halfway over. As far as I know there is only one more event this year focused primarily on fragments, but it’s a biggie, and conferences are already being planned for 2010. Here’s what might be of interest over the next few months.
August 16-20: The fall ACS meeting this year will be held in sweltering Washington, DC. Although there are no sessions devoted exclusively to fragments, a number of FBLD talks and posters are sprinkled throughout the conference.
September 21-23: Much-anticipated FBLD 2009 will be held in historic York, UK. There will also be a one-day workshop on September 20 to provide an overview of fragment-based drug discovery for newcomers to the field. The draft schedule for the conference has just been released (pdf) – looks like a great lineup, so if you missed the earlier conferences this year, don’t miss this one!
2010
February 3-5: CHI’s Molecular Medicine Tri-Conference is being held in the beautiful city of San Francisco, with a track on medicinal chemistry that will probably have some fragment talks, and a fragment workshop on February 2.
March 21-25: The spring ACS meeting will be in foggy (but beautiful) San Francisco. No schedule or link yet.
April 20-25: The Keystone Symposium on computer-aided drug design will take place in brisk Whistler, British Columbia. Although not exclusively devoted to fragments, the schedule shows plenty of talks on FBLD.
April 26: The CHI fragment-conference will be held in summery San Diego. No web link yet, but I’ll have this when it becomes available.
As always, let us know if we’ve missed anything and we’ll get the word out!
August 16-20: The fall ACS meeting this year will be held in sweltering Washington, DC. Although there are no sessions devoted exclusively to fragments, a number of FBLD talks and posters are sprinkled throughout the conference.
September 21-23: Much-anticipated FBLD 2009 will be held in historic York, UK. There will also be a one-day workshop on September 20 to provide an overview of fragment-based drug discovery for newcomers to the field. The draft schedule for the conference has just been released (pdf) – looks like a great lineup, so if you missed the earlier conferences this year, don’t miss this one!
2010
February 3-5: CHI’s Molecular Medicine Tri-Conference is being held in the beautiful city of San Francisco, with a track on medicinal chemistry that will probably have some fragment talks, and a fragment workshop on February 2.
March 21-25: The spring ACS meeting will be in foggy (but beautiful) San Francisco. No schedule or link yet.
April 20-25: The Keystone Symposium on computer-aided drug design will take place in brisk Whistler, British Columbia. Although not exclusively devoted to fragments, the schedule shows plenty of talks on FBLD.
April 26: The CHI fragment-conference will be held in summery San Diego. No web link yet, but I’ll have this when it becomes available.
As always, let us know if we’ve missed anything and we’ll get the word out!
18 April 2009
Updated Again: Fragment Events in 2009
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.
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.
06 February 2009
Updated: Fragment Events in 2009
Here’s an updated schedule of known fragment events this year. Some of these have been previously discussed in more detail (here, and here) and are just highlighted briefly below.
February 24 and 25-27: CHI Molecular Medicine Tri-Conference, San Francisco, CA and FBDD short course
February 26: The New York Academy of Sciences is holding a symposium in New York City on “Molecular Diversity in Chemical Biology and Drug Discovery”, at which I’ll be giving a general talk on FBDD. Please come and introduce yourself!
March 4-5: Royal Society of Chemistry’s Fragments 2009, Alderley Park, UK
March 22-26: A full one and a half day session on “Library Design, Search Methods and Applications of Fragment-based Drug Design” is being held at the 237th American Chemical Society National Meeting and Exposition, in Salt Lake City, Utah. There are also a number of fragment-themed talks and posters scattered throughout the conference. ACS meetings are massive, sprawling affairs, but there’s always plenty of great science on tap.
April 7-8: CHI’s Fragment-Based Techniques, San Diego
September 21-23: FBLD 2009, York, UK
Know of anything else? Let us know and we’ll get the word out!
February 24 and 25-27: CHI Molecular Medicine Tri-Conference, San Francisco, CA and FBDD short course
February 26: The New York Academy of Sciences is holding a symposium in New York City on “Molecular Diversity in Chemical Biology and Drug Discovery”, at which I’ll be giving a general talk on FBDD. Please come and introduce yourself!
March 4-5: Royal Society of Chemistry’s Fragments 2009, Alderley Park, UK
March 22-26: A full one and a half day session on “Library Design, Search Methods and Applications of Fragment-based Drug Design” is being held at the 237th American Chemical Society National Meeting and Exposition, in Salt Lake City, Utah. There are also a number of fragment-themed talks and posters scattered throughout the conference. ACS meetings are massive, sprawling affairs, but there’s always plenty of great science on tap.
April 7-8: CHI’s Fragment-Based Techniques, San Diego
September 21-23: FBLD 2009, York, UK
Know of anything else? Let us know and we’ll get the word out!
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