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The Curious Wavefunction
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- September 17, 2010
- 01:37 PM
- 1,253 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
- April 14, 2009
- 04:36 PM
- 1,164 views
Much ado about protein dynamics
by The Curious Wavefunction in The Curious Wavefunction
Let me alert you, in case you haven't noticed, to the latest issue of Science which is a special issue on protein dynamics. There is much of merit here, but this article is especially relevant to drug discovery. It talks about the interaction of small molecules and how it reshapes the energy landscape of protein conformational motion. One of the most useful ways of thinking about small molecule-protein interactions is to visualize a protein that fluctuates between several conformational states w........ Read more »
Lee, G., & Craik, C. (2009) Trapping Moving Targets with Small Molecules. Science, 324(5924), 213-215. DOI: 10.1126/science.1169378
- April 2, 2010
- 02:44 PM
- 1,142 views
Will virtual screening ever work?
by The Curious Wavefunction in The Curious Wavefunction
Virtual screening (VS), wherein a large number of compounds are screened, either by docking against a protein target of interest or by similarity searching against a known active, is one of the most popular computational techniques in drug discovery. The goal of VS is to complement high-throughput screening (HTS) and the ideal goal is to at least partly substitute HTS in finding new hits.But this goal is still far from being achieved. VS still has to make a significant contribution in the discov........ Read more »
Schneider, G. (2010) Virtual screening: an endless staircase?. Nature Reviews Drug Discovery, 9(4), 273-276. DOI: 10.1038/nrd3139
- February 24, 2010
- 04:24 PM
- 1,101 views
Intramolecular hydrogen bonds in medicinal chemistry
by The Curious Wavefunction in The Curious Wavefunction
In the latest issue of J. Med. Chem., researchers from Roche in Basel have a nice analysis of intramolecular hydrogen bonds in druglike molecules. An internal hydrogen bond can intuitively confer an important property on a drug; it can make the drug more lipophilic by shielding the hydrogen bonding groups from solvent and render it more lipophilic. Thus, intramolecular h-bonding has emerged as a useful strategy in improving membrane permeability.The authors look at both the CSD and the PDB and d........ Read more »
Kuhn, B., Mohr, P., & Stahl, M. (2010) Intramolecular Hydrogen Bonding in Medicinal Chemistry. Journal of Medicinal Chemistry, 2147483647. DOI: 10.1021/jm100087s
- October 27, 2010
- 02:30 PM
- 1,054 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
- June 17, 2009
- 10:04 PM
- 1,033 views
So what exactly are force fields good for?
by The Curious Wavefunction in The Curious Wavefunction
Sue Storm tries hard to use her favorite force field to counter the 1 kcal/mol barrierEvery once in a while there is a study asking what method X (X = docking, free energy calculations, molecular dynamics, force fields etc.) is good for. Such studies can be useful to take stock of a particular paradigm. So the question that Jonathan Goodman and his group ask in this paper is "Are force fields good for reproducing non-bonded interactions, especially hydrogen bonding, pi-stacking and dispersion?"......... Read more »
Paton, R., & Goodman, J. (2009) Hydrogen Bonding and π-Stacking: How Reliable are Force Fields? A Critical Evaluation of Force Field Descriptions of Nonbonded Interactions. Journal of Chemical Information and Modeling, 49(4), 944-955. DOI: 10.1021/ci900009f
- February 1, 2009
- 10:24 AM
- 1,027 views
A Drug Design Class Act: ∆S or ∆H?
by The Curious Wavefunction in The Curious Wavefunction
One of the most important relations in all of chemistry is the free energy relation ∆G = ∆H - T∆S. Tuning the potency of a ligand binding to a protein involves a fine balance between optimizing both entropy and enthalpy. In his review on the role of these two variables, Johns Hopkins's Ernesto Freire makes a very interesting observation; that for a given series of progressively improved set of drugs binding to a given protein, it's the enthalpy that becomes more and more favourable while t........ Read more »
E Freire. (2008) Do enthalpy and entropy distinguish first in class from best in class?. Drug Discovery Today, 13(19-20), 869-874. DOI: 10.1016/j.drudis.2008.07.005
- March 29, 2010
- 10:03 AM
- 1,011 views
How useful is cheminformatics in drug discovery?
by The Curious Wavefunction in The Curious Wavefunction
Just like bioinformatics, cheminformatics has come into its own an independent framework and tool for drug design. As a measure of the field's independence and importance, consider that at least five journals primarily dedicated to it have emerged in the last couple of years, and 15000 articles on it have been published since 2003.But how useful is it in drug discovery? The answer, just like for other approaches and technologies, is that it depends. For calculating and analyzing some properties ........ Read more »
Muchmore, S., Edmunds, J., Stewart, K., & Hajduk, P. (2010) Cheminformatic Tools for Medicinal Chemists. Journal of Medicinal Chemistry, 2147483647. DOI: 10.1021/jm100164z
- July 12, 2010
- 10:05 AM
- 987 views
Computational modeling of GPCRs: What are the challenges?
by The Curious Wavefunction in The Curious Wavefunction
GPCRs are extremely important proteins both for pure and applied science research, but they are also very difficult to crystallize and hence structural information on them has been sparse. Naturally in such a case, computational modeling can be expected to be of great value of providing insight into GPCR structure and function. However, even though progress has been impressive, such modeling still has to overcome many challenges. A recent review lists some of them.Firstly, in the absence of crys........ Read more »
Yarnitzky T, Levit A, & Niv MY. (2010) Homology modeling of G-protein-coupled receptors with X-ray structures on the rise. Current opinion in drug discovery , 13(3), 317-25. PMID: 20443165
- March 16, 2009
- 12:18 PM
- 979 views
So salt bridges are not stable in water? Shocking
by The Curious Wavefunction in The Curious Wavefunction
Three salt bridges seen in this protein in the xtal structure were not observed by detailed NMR experiments in water. Here's the abstract: NMR investigations have been carried out on the B1 domain of protein G. This protein has six lysine residues, of which three are consistently found to form surface-exposed salt bridges in crystal structures, while the other three are not. The Nζ and Hζ chemical shifts of all six lysines are similar and are not affected significantly by pH titration of the ........ Read more »
Tomlinson, J., Ullah, S., Hansen, P., & Williamson, M. (2009) Characterization of Salt Bridges to Lysines in the Protein G B1 Domain. Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja808223p
- September 3, 2008
- 09:59 AM
- 955 views
Gernot Frenking is not happy...not at all
by The Curious Wavefunction in The Curious Wavefunction
Stable is simply "able" with a "st"Wow. This is a first for me. Three of the heavyweights in theoretical and computational chemistry have published a set of prescriptions in Angewandte Chemie for theoretical chemists claiming to have discovered new, "stable" molecules. In response, Gernot Frenking who is a well-known chemist himself has not just published a piercing and trenchant critique in reply to this article, but they actually seem to have reproduced the text of his referee's comments as a ........ Read more »
Roald Hoffmann, Paul von Ragué Schleyer, & Henry F. Schaefer III. (2008) Predicting Molecules - More Realism, Please!. Angewandte Chemie International Edition, 47(38), 7164-7167. DOI: 10.1002/anie.200801206
Gernot Frenking. (2008) No Important Suggestions. Angewandte Chemie International Edition, 47(38), 7168-7169. DOI: 10.1002/anie.200802500
- June 14, 2010
- 05:11 PM
- 944 views
The origin of life cannot escape basic organic chemistry
by The Curious Wavefunction in The Curious Wavefunction
One of the key challenges facing any theories of the molecular origins of life concerns the synthesis, stability polymerization and self-assembly of early life's molecular components. If you cannot explain the chemical origin of these components, you cannot really explain the origin of life. In case of life as we know it, this boils down to explaining the origin of the building blocks of living organisms, namely nucleotides and amino acids.The simplest principles and quirks of chemistry could ha........ Read more »
Choudhary, A., Kamer, K., Powner, M., Sutherland, J., & Raines, R. (2010) A Stereoelectronic Effect in Prebiotic Nucleotide Synthesis. ACS Chemical Biology, 2147483647. DOI: 10.1021/cb100093g
- January 24, 2009
- 10:51 PM
- 895 views
Strain Energies in Ligand Binding: Round Two- Fight!
by The Curious Wavefunction in The Curious Wavefunction
Or why to be wary of ligands in the PDB, force field energies, and anybody who tells you not to be wary of these twoOne of the longstanding questions in protein-ligand binding has been; what is the energy penalty that a protein has to pay in order to bind a ligand? Another question is; what is the strain energy that a protein pays in order to bind the protein? Contrary to what one might initially think, the two questions are not the same. Strain energy is the price paid to twist the conformation........ Read more »
Keith T. Butler, F. Javier Luque, & Xavier Barril. (2009) Toward accurate relative energy predictions of the bioactive conformation of drugs. Journal of Computational Chemistry, 30(4), 601-610. DOI: 10.1002/jcc.21087
Emanuele Perola, & Paul S. Charifson. (2004) Conformational Analysis of Drug-Like Molecules Bound to Proteins: An Extensive Study of Ligand Reorganization upon Binding. Journal of Medicinal Chemistry, 47(10), 2499-2510. DOI: 10.1021/jm030563w
A DAVIS, S STGALLAY, & G KLEYWEGT. (2008) Limitations and lessons in the use of X-ray structural information in drug design. Drug Discovery Today, 13(19-20), 831-841. DOI: 10.1016/j.drudis.2008.06.006
- April 15, 2009
- 01:03 PM
- 893 views
The rest is all noise: errors in R values and the greatness of Carl Friedrich Gauss reiterated
by The Curious Wavefunction in The Curious Wavefunction
One of the questions seldom asked when building a model or assessing experimental data is "What's the error in that?". Unless we know the errors in the measurement of a variable, fitting predicted to experimental values may be a flawed endeavor. For instance when one expects a linear relationship between calculated and experimental values and does not see it, it could either mean that there is a flaw in the underlying expectation or calculation (commonly deduced) or that there is a problem with ........ Read more »
Brown, S., Muchmore, S., & Hajduk, P. (2009) Healthy skepticism: assessing realistic model performance. Drug Discovery Today, 14(7-8), 420-427. DOI: 10.1016/j.drudis.2009.01.012
- April 29, 2010
- 01:29 PM
- 872 views
Steering library bias toward adenosine A2A receptor ligand discovery
by The Curious Wavefunction in The Curious Wavefunction
The A2A adenosine receptor is an important GPCR, well-known for binding caffeine. Adenosine receptors are emerging as relevant drug targets for a variety of disorders including Parkinson's disease, and there is interest in discovering new ligands that bind to them. Among adenosine receptor subtypes, the A2A receptor is one of the few GPCRs whose crystal structure is available. Thus the A2A is amenable to structure-based design efforts, and virtual screening is an especially attractive endeavor i........ Read more »
Carlsson, J., Yoo, L., Gao, Z., Irwin, J., Shoichet, B., & Jacobson, K. (2010) Structure-Based Discovery of A Adenosine Receptor Ligands . Journal of Medicinal Chemistry, 2147483647. DOI: 10.1021/jm100240h
- March 16, 2010
- 10:09 AM
- 860 views
Remote control of peptide screw sense
by The Curious Wavefunction in The Curious Wavefunction
As is well-known, peptides helices can be right or left handed. Many details of structure, amino acid identity and orientation can control this screw sense, and sometimes the controlling factors can be quite subtle. In a JACS communication, Jonathan Clayden (yes, the co-author of the amazing organic chemistry textbook) and his group uncover a surprising factor that controls the helical screw sense and also incorporate a neat "reporter group" to monitor the screw sense.But this reporter group is ........ Read more »
Solà, J., Helliwell, M., & Clayden, J. (2010) N- versus C-Terminal Control over the Screw-Sense Preference of the Configurationally Achiral, Conformationally Helical Peptide Motif Aib GlyAib . Journal of the American Chemical Society, 2147483647. DOI: 10.1021/ja100662d
- March 23, 2009
- 10:55 AM
- 855 views
Meta-substitution: challenging a classic textbook paradigm
by The Curious Wavefunction in The Curious Wavefunction
With my graduate school circus hopefully about to fold up tent, I will leave you with the abstract for this recent interesting Science paper which challenges a classic sophomore organic chemistry notion; that electron donating groups on benzene direct para and ortho substitution in electrophilic aromatic substitution reactions. By using a clever copper catalyst the authors manage to coax an aryl group to neatly substitute meta to an amido substituent, thus effecting a valuable C-H bond arylation........ Read more »
Phipps, R., & Gaunt, M. (2009) A Meta-Selective Copper-Catalyzed C-H Bond Arylation. Science, 323(5921), 1593-1597. DOI: 10.1126/science.1169975
- February 11, 2009
- 01:12 PM
- 834 views
Another entertaining exchange
by The Curious Wavefunction in The Curious Wavefunction
You may remember that Manfred Christl who is emerging as a kind of vigilante of incorrect chemical structure determinations had debunked a previous claim and shown it to be a manifestation of a 100 year old reaction. There he goes again about the structure of some alleged cyclic allenes. But this time accompanied by a firm rebuttal; it's not often that you see the strong word "incorrect" in a scientific publication.Are strained amides, where delocalization of the nitrogen electron lone pairs is ........ Read more »
Manfred Christl, & Bernd Engels. (2009) Stable Five-Membered-Ring Allenes with Second-Row Elements Only: Not Allenes, But Zwitterions. Angewandte Chemie International Edition, 48(9), 1538-1539. DOI: 10.1002/anie.200803476
Vincent Lavallo, C. Adam Dyker, Bruno Donnadieu, & Guy Bertrand. (2009) Are Allenes with Zwitterionic Character Still Allenes? Of Course!. Angewandte Chemie International Edition, 48(9), 1540-1542. DOI: 10.1002/anie.200804909
- September 11, 2010
- 09:56 AM
- 824 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
- February 5, 2010
- 02:56 PM
- 820 views
Scaling further GPCR summits
by The Curious Wavefunction in The Curious Wavefunction
There's a nice review on GPCRs and their continuing challenges in the British Journal of Pharmacology this month. The authors focus on both structural and functional challenges in the characterization of this most important class of signaling proteins. As is well-known, drugs targeting GPCRs generate the highest revenue among all drugs. And given their basic roles in signal transduction, GPCRs are also clearly very important from an academic standpoint. Yet there is a wall of obstacles confronti........ Read more »
Congreve, M., & Marshall, F. (2009) The impact of GPCR structures on pharmacology and structure-based drug design. British Journal of Pharmacology. DOI: 10.1111/j.1476-5381.2009.00476.x
Zheng, H., Loh, H., & Law, P. (2010) Agonist-selective signaling of G protein-coupled receptor: Mechanisms and implications. IUBMB Life. DOI: 10.1002/iub.293
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