78 posts · 69,628 views
Computational chemist doing drug design and discovery. Specific interests include virtual screening, docking, free energy calculations and molecular dynamics. General interests include biochemistry, pharmacology, structural biology, organic chemistry and physics.
The Curious Wavefunction
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- December 22, 2011
- 05:42 PM
- 741 views
Unruly beasts in the jungle of molecular modeling
by The Curious Wavefunction in The Curious Wavefunction
The Journal of Computer-Aided Molecular Design is having a smorgasbord of accomplished modelers reflecting upon the state and future of modeling in drug discovery research and I would definitely recommend anyone - and especially experimentalists - interested in the role of modeling to take a look at the articles. Many of the articles are extremely thoughtful and balanced and take a hard look at the lack of rigorous studies and results in the field; if there was ever a need to make journal articl........ Read more »
Clark, R., & Waldman, M. (2011) Lions and tigers and bears, oh my! Three barriers to progress in computer-aided molecular design. Journal of Computer-Aided Molecular Design. DOI: 10.1007/s10822-011-9504-3
- December 13, 2011
- 10:36 AM
- 559 views
On reproducibility in modeling
by The Curious Wavefunction in The Curious Wavefunction
A recent issue of Science has an article discussing an issue that has been a constant headache for anyone involved with any kind of modeling in drug discovery - the lack of reproducibility in computational science. The author Roger Peng who is a biostatistician at Johns Hopkins talks about modeling standards in general but I think many of his caveats could apply to drug discovery modeling. The problem has been recognized for a few years now but there have been very few concerted efforts to addre........ Read more »
Peng, R. (2011) Reproducible Research in Computational Science. Science, 334(6060), 1226-1227. DOI: 10.1126/science.1213847
- December 7, 2011
- 08:50 PM
- 611 views
Why drug design is like airplane design. And why it isn't.
by The Curious Wavefunction in The Curious Wavefunction
Air travel constitutes the safest mode of travel in the world today. What is even more impressive is the way airplanes are designed by modeling and simulation, sometimes before the actual prototype is built. In fact simulation has been a mainstay in the aeronautical industry for a long time and what seems like a tremendously complex interaction of metal, plastic and the unpredictable movements of air flow can now be reasonably captured in a computer model.In a recent paper, Walter Woltosz of Sim........ Read more »
Woltosz, W. (2011) If we designed airplanes like we design drugs…. Journal of Computer-Aided Molecular Design. DOI: 10.1007/s10822-011-9490-5
- November 28, 2011
- 08:56 PM
- 559 views
The future of computation in drug discovery
by The Curious Wavefunction in The Curious Wavefunction
Computational chemistry as an independent discipline has its roots in theoretical chemistry, itself an outgrowth of the revolutions in quantum mechanics in the 1920s and 30s. Theoretical and quantum chemistry advanced rapidly in the postwar era and led to many protocols for calculating molecular and electronic properties which became amenable to algorithmic implementation once computers came on the scene. Rapid growth in software and hardware in the 80s and 90s led to the transformation of theor........ Read more »
Bajorath, J. (2011) Computational chemistry in pharmaceutical research: at the crossroads. Journal of Computer-Aided Molecular Design. DOI: 10.1007/s10822-011-9488-z
Martin, E., Ertl, P., Hunt, P., Duca, J., & Lewis, R. (2011) Gazing into the crystal ball; the future of computer-aided drug design. Journal of Computer-Aided Molecular Design. DOI: 10.1007/s10822-011-9487-0
Maggiora, G. (2011) Is there a future for computational chemistry in drug research?. Journal of Computer-Aided Molecular Design. DOI: 10.1007/s10822-011-9493-2
- October 31, 2011
- 01:40 PM
- 555 views
Overturning hydrophobic assumptions
by The Curious Wavefunction in The Curious Wavefunction
One of the most fun things about chemistry is that for every laundry list of examples, there is always a counterexample. The counterexample does not really violate any general principles, but it enriches our understanding of the principle by demonstrating its richness and complexity. And it keeps chemists busy.One such key principle is the hydrophobic effect, an effect with an astounding range of applicability, from the origin of life to cake baking to drug design. Textbook definitions will tell........ Read more »
Myslinski, J., DeLorbe, J., Clements, J., & Martin, S. (2011) Protein–Ligand Interactions: Thermodynamic Effects Associated with Increasing Nonpolar Surface Area. Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja2068752
- October 11, 2011
- 08:49 PM
- 632 views
GPCR modeling: The devil hasn't left the details
by The Curious Wavefunction in The Curious Wavefunction
The last decade has been a bonanza decade for the elucidation of structures of G Protein-Coupled Receptors (GPCRs), culminating with the landmark structure of the first GPCR-G protein complex published a few weeks ago. With 30% of all drugs targeting these proteins and their involvement in virtually every key aspect of health and disease, GPCRs remain glowingly important targets for pure and applied science.Yet there are miles to go before we sleep. Although we now have more than a dozen structu........ Read more »
Carlsson, J., Coleman, R., Setola, V., Irwin, J., Fan, H., Schlessinger, A., Sali, A., Roth, B., & Shoichet, B. (2011) Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nature Chemical Biology. DOI: 10.1038/nchembio.662
- August 19, 2011
- 02:55 PM
- 759 views
The barrier to amyloid formation is kinetic, not thermodynamic
by The Curious Wavefunction in The Curious Wavefunction
One of the questions I have pondered in the past is why the functional form of a protein should correspond to its most thermodynamically stable structure. Although this assumption is built into almost all experimental and theoretical studies of protein folding, it is not at all obvious since one may imagine other forms which could have improved stability. For instance, two protein forms may differ in the presence of a hydrogen bond or two. Based on the location and connectivity of these bonds, s........ Read more »
Baldwin, A., Knowles, T., Tartaglia, G., Fitzpatrick, A., Devlin, G., Shammas, S., Waudby, C., Mossuto, M., Meehan, S., Gras, S.... (2011) Metastability of Native Proteins and the Phenomenon of Amyloid Formation. Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja2017703
- June 29, 2011
- 09:56 AM
- 1,240 views
The protein folding funnel and its discontents
by The Curious Wavefunction in The Curious Wavefunction
Speaking of protein folding, here's something interesting. One of the most enduring views of protein folding from the last decade is that of an "energy funnel". The funnel was invented by the UCSD chemist Peter Wolynes in the 90s (the original paper is highly readable) and essentially depicts a plot of the configurational enthalpy (or effective energy) of the protein on the Y axis vs the configurational entropy on the X axis. In real situations this plot is multidimensional.The funnel suggests ........ Read more »
Karplus, M. (2011) Behind the folding funnel diagram. Nature Chemical Biology, 7(7), 401-404. DOI: 10.1038/nchembio.565
- May 25, 2011
- 10:50 AM
- 989 views
Why use a cofactor when you can create your own?
by The Curious Wavefunction in The Curious Wavefunction
Blogging has been swamped lately by that miracle called life but I could not help but be drawn to a paper in this week's Science which describes a most unholy and unexpected stabilizing alliance in a protein's innards.Proteins are known to form cross-links such as disulfide bonds to stabilize interactions with ligands and substrates. Any reasonable chemist would expect these kinds of interactions to be mediated between polar residues. But nature usurps us low-lifes once again. In this week's Sci........ Read more »
Cooley, R., Rhoads, T., Arp, D., & Karplus, P. (2011) A Diiron Protein Autogenerates a Valine-Phenylalanine Cross-Link. Science, 332(6032), 929-929. DOI: 10.1126/science.1205687
- May 25, 2011
- 10:50 AM
- 672 views
Xtreme C-H functionalization: Natural Edition
by The Curious Wavefunction in The Curious Wavefunction
Blogging has been swamped lately by that miracle called life but I could not help but be drawn to a paper in this week's Science which describes a most unholy and unexpected stabilizing alliance in a protein's innards.Proteins are known to form cross-links such as disulfide bonds to stabilize interactions with ligands and substrates. Any reasonable chemist would expect these kinds of interactions to be mediated between polar residues. But nature usurps us low-lifes once again. In this week's Sci........ Read more »
Cooley, R., Rhoads, T., Arp, D., & Karplus, P. (2011) A Diiron Protein Autogenerates a Valine-Phenylalanine Cross-Link. Science, 332(6032), 929-929. DOI: 10.1126/science.1205687
- December 22, 2010
- 12:02 PM
- 789 views
New place, new view, slow reactions and the origins of life
by The Curious Wavefunction in The Curious Wavefunction
I have been unable to blog for the past few days because I was busy moving to Chapel Hill for a postdoc at UNC Chapel Hill. I am very excited about this move and my upcoming research which is going to involve protein design and folding. Regular blogging will resume soon. Until then, happy holidays, and I will leave you with the following interesting paper published by a group from my new institution.One of the abiding puzzles in the origin of life is to explain how life arose in the relatively s........ Read more »
Stockbridge, R., Lewis, C., Yuan, Y., & Wolfenden, R. (2010) Impact of temperature on the time required for the establishment of primordial biochemistry, and for the evolution of enzymes. Proceedings of the National Academy of Sciences, 107(51), 22102-22105. DOI: 10.1073/pnas.1013647107
- December 1, 2010
- 08:06 PM
- 943 views
Probing amyloid, one oligomer at a time
by The Curious Wavefunction in The Curious Wavefunction
One of the more important paradigm shifts in our understanding of the Alzheimer’s disease-causing amyloid protein in the last few years has been the recognition of differences between the well known polymer aggregates of amyloid and their smaller, soluble oligomer counterparts. For a long time it was believed that the fully formed 40-42 amino acid protein aggregate found in autopsies was the causative agent in AD, or at least the most toxic one. This understanding has radically changed in the ........ Read more »
Reinke, A., Ung, P., Quintero, J., Carlson, H., & Gestwicki, J. (2010) Chemical Probes That Selectively Recognize the Earliest Aβ Oligomers in Complex Mixtures. Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja106291e
- November 2, 2010
- 10:21 PM
- 827 views
A graceful collapse
by The Curious Wavefunction in The Curious Wavefunction
Vijay Pande's group at Stanford has become well-known for using the collective force of millions of CPUs around the world for simulating protein folding in the project known as Folding@home. One of the enduring challenges in simulating folding has been to sample the long timescales that are common in real-life folding events, and recent breakthroughs have made accessing such time domains realistic. We should expect long protein folding simulations to be within the reach of many non-specialists ........ Read more »
Voelz VA, Bowman GR, Beauchamp K, & Pande VS. (2010) Molecular simulation of ab initio protein folding for a millisecond folder NTL9(1-39). Journal of the American Chemical Society, 132(5), 1526-8. PMID: 20070076
- October 27, 2010
- 02:30 PM
- 1,352 views
Functional selectivity: Nature's Bach concerto
by The Curious Wavefunction in The Curious Wavefunction
One of the great things about Bach’s organ music is how changes of a single note in a whole pattern can have rather dramatic effects on the sound. A unique and potentially very important similar phenomenon has been discovered recently in the area of GPCR research.The understanding of the basic process by which GPCRs transmit signals from the cell exterior to the interior has seen remarkable advances in the last three decades, but much still remains to be deciphered. Our knowledge of signaling ........ Read more »
Mailman, R., & Murthy, V. (2010) Ligand functional selectivity advances our understanding of drug mechanisms and drug discovery. Neuropsychopharmacology, 35(1), 345-346. DOI: 10.1038/npp.2009.117
Kelly, E., Bailey, C., & Henderson, G. (2009) Agonist-selective mechanisms of GPCR desensitization. British Journal of Pharmacology, 153(S1). DOI: 10.1038/sj.bjp.0707604
- October 14, 2010
- 12:29 PM
- 1,073 views
What they found in the virtual screening jungle
by The Curious Wavefunction in The Curious Wavefunction
If successful, virtual screening (VS) promises to become an efficient way to find new pharmaceutical hits, competitive with high-throughput screening (HTS). Briefly, virtual screening screens libraries of millions of compounds to find new and diverse hits, either based on similarity to a known active or by complementarity to a protein binding site. The former protocol is called ligand-based VS (LBVS) and the latter is called structure-based VS (SBVS). In a typical VS campaign, either LBVS or SBV........ Read more »
Ripphausen, P., Nisius, B., Peltason, L., & Bajorath, J. (2010) Quo Vadis, Virtual Screening? A Comprehensive Survey of Prospective Applications. Journal of Medicinal Chemistry, 2147483647. DOI: 10.1021/jm101020z
- September 17, 2010
- 01:37 PM
- 1,564 views
'SAR by C13 NMR'
by The Curious Wavefunction in The Curious Wavefunction
The biggest utility of NMR spectroscopy in drug discovery is in assessing three things; whether a particular ligand binds to a protein, what site on the protein it binds, and what parts of the ligand interact with the protein. Over the last few years a powerful technique named ‘SAR by NMR’ has emerged which is now widely used in ligand screening. In this technique, changes in the resonances of ligand and protein protons are observed to pinpoint the ligand binding site and corresponding resid........ Read more »
Swann, S., Song, D., Sun, C., Hajduk, P., & Petros, A. (2010) Labeled Ligand Displacement: Extending NMR-Based Screening of Protein Targets. ACS Medicinal Chemistry Letters, 1(6), 295-299. DOI: 10.1021/ml1000849
- September 16, 2010
- 01:55 PM
- 632 views
Drugging the cell's best friend
by The Curious Wavefunction in The Curious Wavefunction
The tumor suppressor p53 is one of the cell’s very best friends. Just how good a friend it is becomes apparent when, just like in other relationships, this particular relationship turns sour. p53 is the “master guardian angel” of the genome and constitutes the most frequent genetic alteration in cancer. More than 50% of human tumors contain a mutation in the p53 gene. With this kind of glowing track record, p53 would be a prime target for drugs.It turns out that discovering drugs for p53 i........ Read more »
Basse, N., Kaar, J., Settanni, G., Joerger, A., Rutherford, T., & Fersht, A. (2010) Toward the Rational Design of p53-Stabilizing Drugs: Probing the Surface of the Oncogenic Y220C Mutant. Chemistry , 17(1), 46-56. DOI: 10.1016/j.chembiol.2009.12.011
- September 13, 2010
- 03:08 PM
- 696 views
Fishin' in the membrane
by The Curious Wavefunction in The Curious Wavefunction
Since we were talking about GPCRs the other day, here's a nice overview of some of the experimental challenges associated with membrane proteins and how researchers are trying to overcome them. These challenges are associated not just with the crystallization, but with the whole shebang. Although many clever tricks have emerged, we have a long way to go, and at least a few of the tricks sound like brute trial and error.To begin with, it's not that easy to get your expression system to produce am........ Read more »
Baker, M. (2010) Making membrane proteins for structures: a trillion tiny tweaks. Nature Methods, 7(6), 429-434. DOI: 10.1038/nmeth0610-429
- September 11, 2010
- 09:56 AM
- 1,138 views
Why modeling GPCRs is (still) hard
by The Curious Wavefunction in The Curious Wavefunction
Well, it's hard for several reasons which I have discussed in previous posts, but here's one reason demonstrated by a recent paper. In this paper they crystallized the ß2 adrenergic receptor with an antagonist. Previously, in the landmark publication of the ß2 structure in 2007, the protein had been crystallized with an inverse agonist. Recall that an inverse agonist inhibits the basal activity of the GPCR whereas an antagonist stabilizes both active and inactive states but does not affect the........ Read more »
Wacker, D., Fenalti, G., Brown, M., Katritch, V., Abagyan, R., Cherezov, V., & Stevens, R. (2010) Conserved Binding Mode of Human β Adrenergic Receptor Inverse Agonists and Antagonist Revealed by X-ray Crystallography . Journal of the American Chemical Society, 132(33), 11443-11445. DOI: 10.1021/ja105108q
- September 3, 2010
- 10:43 AM
- 1,065 views
My E. coli brother's keeper
by The Curious Wavefunction in The Curious Wavefunction
Would an anti-indole work?Antibiotic resistance is one of the best examples of evolution in real-time and it’s also one of the most serious medical problems of our time. Emerging resistance in bacteria like MRSA threatens to bring on a wave of epidemics that may remind us of past, more unseemly times.Given the threat that antibiotic resistance poses, it is paramount to understand the mechanisms behind this process. While considerable progress has been made in understanding the genetic basis of........ Read more »
Lee HH, Molla MN, Cantor CR, & Collins JJ. (2010) Bacterial charity work leads to population-wide resistance. Nature, 467(7311), 82-5. PMID: 20811456
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