This year ends with an entire issue of Current Topics in Medicinal Chemistry devoted to FBDD. Rob van Montfort and Ian Collins provide a brief editorial overview of the six papers. Collins and colleagues also describe their application of fragment-based methods to develop inhibitors of the anti-cancer target protein kinase B (AKT).
Half the papers cover various forms of fragment screening: the Medical Structural Genomics of Pathogenic Protozoa Consortium describes their crystallographic approach, Helena Danielson discusses the use of SPR, and Gregg Siegal and Johan Hollander present their Target Immobilized NMR Screening (TINS) methodology.
Charles Reynolds and colleagues review metrics, such as ligand efficiency and fit quality, for evaluating fragment hits.
Finally, in the longest article in the collection, Vicki Nienaber discusses how fragment-based methods may be particularly useful for discovering compounds that will cross the blood-brain-barrier to target the central nervous system.
As 2009 comes to a close, Practical Fragments would like to thank our readers, old and new. May you all have a happy and productive 2010!
31 December 2009
21 December 2009
Fragment-based conferences in 2010
There have been some great conferences this past year (see summaries of some of them here and here), and 2010 is shaping up nicely, particularly with the announcement of FBLD 2010 (below).
February 3-5: CHI’s Molecular Medicine Tri-Conference will be held in my beautiful city of San Francisco, with a program on medicinal chemistry that includes a fragment track, 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.”
April 20-25: The Keystone Symposium on computer-aided drug design will take place in Whistler, British Columbia. Although not exclusively devoted to fragments, the schedule shows plenty of talks on the topic.
April 27-28: Cambridge Healthtech Institute’s Fifth Annual Fragment-Based Drug Discovery will be held in San Diego. And if you missed the short course in San Francisco, you have another chance on April 26.
June 6-9: The 32nd National Medicinal Chemistry Symposium will be held in Minneapolis, Minnesota, and Dave Rees is organizing a session on fragments on June 9. Looks like a great lineup, with top speakers from Astex, Plexxikon, Novartis, Abbott, and UC Berkeley.
October 10-13: Finally, standing alone in the second half of the year, Fragment-based Lead Discovery 2010 will be held in Philadelphia, PA. This is the third in a popular series of conferences that started with FBLD 2008 in San Diego and continued this year in York, UK. An emphasis next year will be on biophysical methods - old and new - for fragment identification and characterization, as well as sessions on libraries, chemical strategies for fragment evolution, and success stories. A web site will be available shortly where further details will be posted. We anticipate a call for oral and poster contributions during the Spring of 2010. As far as we know this is the first major fragment event on the east coast of the US, so don't miss it!
Know of anything else? Organizing a fragment event? Let us know and we’ll get the word out.
February 3-5: CHI’s Molecular Medicine Tri-Conference will be held in my beautiful city of San Francisco, with a program on medicinal chemistry that includes a fragment track, 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.”
April 20-25: The Keystone Symposium on computer-aided drug design will take place in Whistler, British Columbia. Although not exclusively devoted to fragments, the schedule shows plenty of talks on the topic.
April 27-28: Cambridge Healthtech Institute’s Fifth Annual Fragment-Based Drug Discovery will be held in San Diego. And if you missed the short course in San Francisco, you have another chance on April 26.
June 6-9: The 32nd National Medicinal Chemistry Symposium will be held in Minneapolis, Minnesota, and Dave Rees is organizing a session on fragments on June 9. Looks like a great lineup, with top speakers from Astex, Plexxikon, Novartis, Abbott, and UC Berkeley.
October 10-13: Finally, standing alone in the second half of the year, Fragment-based Lead Discovery 2010 will be held in Philadelphia, PA. This is the third in a popular series of conferences that started with FBLD 2008 in San Diego and continued this year in York, UK. An emphasis next year will be on biophysical methods - old and new - for fragment identification and characterization, as well as sessions on libraries, chemical strategies for fragment evolution, and success stories. A web site will be available shortly where further details will be posted. We anticipate a call for oral and poster contributions during the Spring of 2010. As far as we know this is the first major fragment event on the east coast of the US, so don't miss it!
Know of anything else? Organizing a fragment event? Let us know and we’ll get the word out.
15 December 2009
Natural linking – though not of fragments
We’ve previously discussed the appeal and challenges of fragment linking. A new paper in Science describes how a naturally occurring antibiotic makes use of a linking strategy, albeit using rather Brobdingnagian fragments.
Simocyclinone D8 (SD8) is a dumbbell shaped molecule isolated several years ago from that ultimate micro-pharma, Streptomyces. Although SD8 blocks the action of bacterial DNA gyrase, which is also the target of fluoroquinolones such as ciprofloxacin and aminocoumarins such as novobiocin, it is mechanistically distinct from these older antibiotics. To understand why, Anthony Maxwell and colleagues at the John Innes Centre in Norwich, UK, solved the co-crystal structure of SD8 bound to GyrA. The structure reveals that the protein forms a dimer of dimers, with four molecules of SD8 bound to the four subunits of GyrA. Weirdly, each molecule of SD8 cross-links two separate subunits of GyrA, although mass-spectrometry, analytical ultracentrifugation, and modeling suggest that a single molecule of SD8 could also bind to a single GyrA subunit. The crystal structure shows that SD8 binds near – but not at – the fluoroquinolone binding site, blocking the DNA-binding portion of GyrA.
What caught my eye is the fact that both halves of the molecule are active by themselves, albeit with a loss in potency (see figure). The linker is over one nanometer long and doesn’t appear to make significant interactions with the protein; it would be fun to know how something like this evolved.
Antibiotics gleefully seem to ignore the Rule of 5, but it wouldn’t hurt to get a smaller, less complicated analog. Replacing either of the two ends with smaller fragments may be a productive approach, as would optimizing the individual “fragments” themselves.
Simocyclinone D8 (SD8) is a dumbbell shaped molecule isolated several years ago from that ultimate micro-pharma, Streptomyces. Although SD8 blocks the action of bacterial DNA gyrase, which is also the target of fluoroquinolones such as ciprofloxacin and aminocoumarins such as novobiocin, it is mechanistically distinct from these older antibiotics. To understand why, Anthony Maxwell and colleagues at the John Innes Centre in Norwich, UK, solved the co-crystal structure of SD8 bound to GyrA. The structure reveals that the protein forms a dimer of dimers, with four molecules of SD8 bound to the four subunits of GyrA. Weirdly, each molecule of SD8 cross-links two separate subunits of GyrA, although mass-spectrometry, analytical ultracentrifugation, and modeling suggest that a single molecule of SD8 could also bind to a single GyrA subunit. The crystal structure shows that SD8 binds near – but not at – the fluoroquinolone binding site, blocking the DNA-binding portion of GyrA.
What caught my eye is the fact that both halves of the molecule are active by themselves, albeit with a loss in potency (see figure). The linker is over one nanometer long and doesn’t appear to make significant interactions with the protein; it would be fun to know how something like this evolved.
Antibiotics gleefully seem to ignore the Rule of 5, but it wouldn’t hurt to get a smaller, less complicated analog. Replacing either of the two ends with smaller fragments may be a productive approach, as would optimizing the individual “fragments” themselves.
12 December 2009
Warren DeLano Memorial Award
We wrote last month about Warren DeLano, and in the December issue of Nature Structural and Molecular Biology Axel Brunger and Jim Wells have written a beautiful obituary.
Together with Warren’s family, Axel and Jim are also organizing a commemorative fund:
The Warren L. DeLano Memorial Award for Computational Biosciences
To endow this in perpetuity would require about $100,000, and the fund is off to a good start, with $23,000 contributed and another $30,000 pledged so far.
Together with Warren’s family, Axel and Jim are also organizing a commemorative fund:
The Warren L. DeLano Memorial Award for Computational Biosciences
This award shall be given to a top computational bioscientist in recognition of the contributions made by Warren L. DeLano to creating powerful visualization tools for three dimensional structures and making them freely accessible. The award, accompanying lecture, and honorium will be given annually in the context of a national bioscience meeting or a Bay Area gathering of computational bioscientists at Stanford, UCSF or UC Berkeley. For the award special emphasis will be given for Open Source developments and service to the bioscience community.
For the award selection, a committee will be formed consisting of experts in the computational and biological sciences. Submission for nominations will be open to everybody.
Tax deductible donations can be made by check to the address below or by PayPal.
Silicon Valley Community Foundation
memo: Warren L. DeLano Memorial Fund
2440 West El Camino Real, Suite 300
Mountain View, CA 94040
tel: 650.450.5400
To endow this in perpetuity would require about $100,000, and the fund is off to a good start, with $23,000 contributed and another $30,000 pledged so far.
03 December 2009
Enthalpy versus entropy
The earliest stages of lead discovery usually focus on obtaining a molecule with decent affinity for a given target. Affinity, or binding energy, can be dissected into two components: enthalpy and entropy. On a (very) simplistic level, enthalpic binding comes via specific molecular interactions, such as hydrogen bonds, while entropic binding results from nonspecific hydrophobic interactions. Optimizing enthalpy is usually more difficult than optimizing entropy: engineering a polar interaction requires more precision than adding a bit of grease. In a new paper in ChemMedChem, Andrew Scott and colleagues at Pfizer show how fragments that owe more of their binding affinity to enthalpy make better starting points for optimization than do fragments whose binding is more entropic, even if the entropic fragment is more potent.
The researchers used human carbonic anhydrase (hCA II), a venerable work-horse of biophysical studies. Benzenesulfonamide (compound 1, below) is a known binder, and the researchers studied the thermodynamics of 20 derivatives of this molecule using isothermal titration calorimetry (ITC), taking care to generate high-quality binding data. Adding a fluorine group to the 2-position of benzenesulfonamide (compound 2) improves the potency almost three-fold but lowers the ligand efficiency. In contrast, adding a fluorine to the 3-position (compound 3) improves the potency by seven-fold and also improves the ligand efficiency.
If you were choosing between these fragments solely on the basis of affinity or ligand efficiency, it would be reasonable to choose compound 3, and in fact a search of the literature turned up 15 carbonic anhydrase inhibitors that contained the 3-fluorobenzenesulfonamide substructure and none that contained the 2-flurobenzenesulfonamide substructure. However, a look at the thermodynamic parameters reveals that the affinity of compound 2 is driven by a sizable improvement in enthalpic binding, partially offset by lowered entropy. In contrast, compound 3 has a similar enthalpy of binding as compound 1 but increased entropy. What’s going on?
The researchers determined high-resolution crystal structures for all three of these molecules bound to hCA II. Interestingly, the structure of compound 2 shows a specific interaction between the fluorine atom and a main-chain NH of the protein. In compound 3, the fluorine points towards the hydrophobic wall of the protein.
Adding a 4-benzylamide substituent onto each of these molecules led to improvements in activity. However, this was a relatively modest boost for the more entropic compound 3 to compound 20, but considerably larger for the enthaplically-driven compound 2 to compound 19. Compound 19 shows a highly favorable binding enthalpy, and is the most potent and ligand-efficient of any of the three elaborated molecules.
Obtaining thermodynamic parameters for small-molecule protein interactions has historically been challenging, but in recent years miniaturization and improvements in technology have brought ITC into more non-specialist labs. If you have the resources, it may be worthwhile characterizing the thermodynamic profiles of your fragment hits, and – perhaps – looking more closely at those that show enthalpically-driven binding.
The researchers used human carbonic anhydrase (hCA II), a venerable work-horse of biophysical studies. Benzenesulfonamide (compound 1, below) is a known binder, and the researchers studied the thermodynamics of 20 derivatives of this molecule using isothermal titration calorimetry (ITC), taking care to generate high-quality binding data. Adding a fluorine group to the 2-position of benzenesulfonamide (compound 2) improves the potency almost three-fold but lowers the ligand efficiency. In contrast, adding a fluorine to the 3-position (compound 3) improves the potency by seven-fold and also improves the ligand efficiency.
If you were choosing between these fragments solely on the basis of affinity or ligand efficiency, it would be reasonable to choose compound 3, and in fact a search of the literature turned up 15 carbonic anhydrase inhibitors that contained the 3-fluorobenzenesulfonamide substructure and none that contained the 2-flurobenzenesulfonamide substructure. However, a look at the thermodynamic parameters reveals that the affinity of compound 2 is driven by a sizable improvement in enthalpic binding, partially offset by lowered entropy. In contrast, compound 3 has a similar enthalpy of binding as compound 1 but increased entropy. What’s going on?
The researchers determined high-resolution crystal structures for all three of these molecules bound to hCA II. Interestingly, the structure of compound 2 shows a specific interaction between the fluorine atom and a main-chain NH of the protein. In compound 3, the fluorine points towards the hydrophobic wall of the protein.
Adding a 4-benzylamide substituent onto each of these molecules led to improvements in activity. However, this was a relatively modest boost for the more entropic compound 3 to compound 20, but considerably larger for the enthaplically-driven compound 2 to compound 19. Compound 19 shows a highly favorable binding enthalpy, and is the most potent and ligand-efficient of any of the three elaborated molecules.
Obtaining thermodynamic parameters for small-molecule protein interactions has historically been challenging, but in recent years miniaturization and improvements in technology have brought ITC into more non-specialist labs. If you have the resources, it may be worthwhile characterizing the thermodynamic profiles of your fragment hits, and – perhaps – looking more closely at those that show enthalpically-driven binding.
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