78 posts · 70,544 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
78 posts
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- August 30, 2010
- 05:38 PM
- 595 views
Assessing computationally designed enzymes
by The Curious Wavefunction in The Curious Wavefunction
One of the most promising recent developments in computational biochemistry is the development of potential capability to design entirely new enzymes that can perform reactions inaccessible to naturally occurring proteins. Such enzymes can be of great utility as novel biofuels, synthetic reagents and new drugs. A particularly noteworthy set of publications in this regard were from David Baker’s and Ken Houk’s groups in Seattle and Los Angeles. In 2008, the groups designed an enzyme for perfo........ Read more »
Kiss, G., Röthlisberger, D., Baker, D., & Houk, K. (2010) Evaluation and ranking of enzyme designs. Protein Science. DOI: 10.1002/pro.462
- August 5, 2010
- 10:04 AM
- 967 views
Humans beat computers in predicting protein structures
by The Curious Wavefunction in The Curious Wavefunction
I was going to first describe Rosetta in a post, but a rather cool paper related to the program which appeared in Nature yesterday makes me jump the gun.In a nutshell, Rosetta tries to predict the structure of proteins from amino acid sequence by inserting fragments from known protein structures and doing many rounds of side chain torsional angle and rigid-body energy optimization. It uses a scoring function to rank the resulting structures that uses empirically derived hydrogen bonding, hydroph........ Read more »
Cooper, S., Khatib, F., Treuille, A., Barbero, J., Lee, J., Beenen, M., Leaver-Fay, A., Baker, D., Popović, Z., & players, F. (2010) Predicting protein structures with a multiplayer online game. Nature, 466(7307), 756-760. DOI: 10.1038/nature09304
- July 12, 2010
- 10:05 AM
- 1,237 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
- June 14, 2010
- 05:11 PM
- 1,241 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
- May 25, 2010
- 08:34 AM
- 675 views
A shot in the arm for antimalarial drug discovery?
by The Curious Wavefunction in The Curious Wavefunction
While heart disease, cancer and Alzheimer's continue to grab the headlines, malaria and tuberculosis continue to quietly do their deadly work behind the scenes. Diseases that disproportionately affect sub-Saharan Africa are not exactly priorities for drug companies. But they pose a tremendous unmet need. Especially malaria, which kills an unbelievable 800,000 people every year, has fought back against almost every traditional drug. The fight against the disease has boiled down to one class of dr........ Read more »
Guiguemde, W., Shelat, A., Bouck, D., Duffy, S., Crowther, G., Davis, P., Smithson, D., Connelly, M., Clark, J., Zhu, F.... (2010) Chemical genetics of Plasmodium falciparum. Nature, 465(7296), 311-315. DOI: 10.1038/nature09099
Gamo, F., Sanz, L., Vidal, J., de Cozar, C., Alvarez, E., Lavandera, J., Vanderwall, D., Green, D., Kumar, V., Hasan, S.... (2010) Thousands of chemical starting points for antimalarial lead identification. Nature, 465(7296), 305-310. DOI: 10.1038/nature09107
- May 3, 2010
- 04:42 PM
- 954 views
It's truly the entropy that binds us together
by The Curious Wavefunction in The Curious Wavefunction
Fragment-based Drug Design (FBDD) has emerged as one of the key strategies in drug design during the past two decades. FBDD hinges on the fact that fragments, as opposed to complete ligands, are easier to optimize and study since they possess lesser molecular complexity and have fewer binding interactions.When fragments are optimized to bind to parts of a protein's active site, they can gain powerful binding affinity by being linked together. Usually fragments are relatively weak binders, and co........ Read more »
Borsi, V., Calderone, V., Fragai, M., Luchinat, C., & Sarti, N. (2010) Entropic Contribution to the Linking Coefficient in Fragment Based Drug Design: A Case Study. Journal of Medicinal Chemistry, 2147483647. DOI: 10.1021/jm901723z
- April 29, 2010
- 01:29 PM
- 1,078 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
- April 27, 2010
- 10:24 AM
- 495 views
It's (not) the mutation, stupid
by The Curious Wavefunction in The Curious Wavefunction
Cancer has emerged as a fundamentally genetic disease, where mutations in genes cause cells to go haywire. Yet, finding out exactly which mutations are responsible for a certain type of cancer is a daunting task. A recent report in Nature which details the cataloging of tens of thousands of mutations in tens of thousands of tumors illustrates the merits and dangerous pitfalls of such an approach.The article talks about the International Cancer Genome Consortium (ICGC), formed in 2008, whose task........ Read more »
Ledford, H. (2010) Big science: The cancer genome challenge. Nature, 464(7291), 972-974. DOI: 10.1038/464972a
- April 2, 2010
- 02:44 PM
- 1,371 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
- March 29, 2010
- 10:03 AM
- 1,196 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
- March 16, 2010
- 10:09 AM
- 983 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 9, 2010
- 03:09 PM
- 510 views
Screening probes and probing screens
by The Curious Wavefunction in The Curious Wavefunction
High Throughput Screening (HTS), with all its strengths and limitations, is still the single-best way to discover novel interesting molecules in drug discovery. Thomas Kodadek of Scripps Florida has an interesting article on screening in the latest issue of Nat. Chem. Biol which is a special issue on chemical probes. Kodadek talks about the very different properties required for drugs and probes and the limitations and unmet needs in current HTS strategies. He focuses on mainly two kinds of scre........ Read more »
Kodadek, T. (2010) Rethinking screening. Nature Chemical Biology, 6(3), 162-165. DOI: 10.1038/nchembio.303
- February 24, 2010
- 04:24 PM
- 1,308 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
- February 5, 2010
- 02:56 PM
- 993 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
- February 1, 2010
- 01:25 PM
- 687 views
Simulations long enough to...put you to sleep
by The Curious Wavefunction in The Curious Wavefunction
For something as widely used for as long as general anesthetics (GAs), one would think that their molecular mechanism of action would have been fairly understood. Far from it. From Linus Pauling's theory of gases like xenon acting at high concentrations by forming clathrates to more recent theories of GA action on lipids and now on proteins, tantalizing clues have emerged, but speculation remains rife. In a recent Acc. Chem. Res. review, a group of researchers explains some recent studies on GA ........ Read more »
Vemparala, S., Domene, C., & Klein, M. (2010) Computational Studies on the Interactions of Inhalational Anesthetics with Proteins. Accounts of Chemical Research, 43(1), 103-110. DOI: 10.1021/ar900149j
- November 30, 2009
- 07:50 PM
- 810 views
More model perils; parametrize this
by The Curious Wavefunction in The Curious Wavefunction
Now here's a very interesting review article that puts some of the pitfalls of models that I have mentioned on these pages in perspective. The article is by Jack Dunitz and his long-time colleague Angelo Gavezzotti. Dunitz is in my opinion one of the finest chemists and technical writers of the last half century and I have learnt a lot from his articles. Two that are on my "top 10" list are his article showing the entropic gain accrued by displacing water molecules in crystals and proteins (a ma........ Read more »
Dunitz, J., & Gavezzotti, A. (2009) How molecules stick together in organic crystals: weak intermolecular interactions. Chemical Society Reviews, 38(9), 2622. DOI: 10.1039/b822963p
- November 11, 2009
- 06:12 PM
- 831 views
Constancy of the discodermolide hairpin motif
by The Curious Wavefunction in The Curious Wavefunction
Our paper on the conformational analysis of discodermolide is now up on the ACS website. The following is a brief description of the work.Discodermolide (DDM) is a well-known highly flexible polyketide that is the most potent microtubule polymerization agent known. In this capacity it functions very similar to taxol and the epothilones. However the binding mode of DDM will intimately depend on its conformations in solution. To this end we have performed multiple force field conformational search........ Read more »
Jogalekar, A., Kriel, F., Shi, Q., Cornett, B., Cicero, D., & Snyder, J. (2009) The Discodermolide Hairpin Structure Flows from Conformationally Stable Modular Motifs. Journal of Medicinal Chemistry, 2147483647. DOI: 10.1021/jm9015284
- November 11, 2009
- 06:12 PM
- 724 views
Constancy of the discodermolide hairpin motif
by The Curious Wavefunction in The Curious Wavefunction
Our paper on the conformational analysis of discodermolide is now up on the ACS website. The following is a brief description of the work.Discodermolide (DDM) is a well-known highly flexible polyketide that is the most potent microtubule polymerization agent known. In this capacity it functions very similar to taxol and the epothilones. However the binding mode of DDM will intimately depend on its conformations in solution. To this end we have performed multiple force field conformational search........ Read more »
Jogalekar, A., Kriel, F., Shi, Q., Cornett, B., Cicero, D., & Snyder, J. (2009) The Discodermolide Hairpin Structure Flows from Conformationally Stable Modular Motifs. Journal of Medicinal Chemistry, 2147483647. DOI: 10.1021/jm9015284
- October 27, 2009
- 08:30 PM
- 789 views
Tautomers need some love
by The Curious Wavefunction in The Curious Wavefunction
Now here's a paper about something that every college student knows about and which is yet not considered by people who do drug design as often as it should- tautomers. Yvonne Martin (previously at Abbott) has a nice article about why tautomers are important in drug design and what are the continuing challenges in predicting and understanding them. This should be a good reminder for both experimentalists and theoreticians to consider tautomerism in their projects.So why are tautomers important? ........ Read more »
Martin, Y. (2009) Let’s not forget tautomers. Journal of Computer-Aided Molecular Design. DOI: 10.1007/s10822-009-9303-2
- October 27, 2009
- 08:30 PM
- 763 views
Tautomers need some love
by The Curious Wavefunction in The Curious Wavefunction
Now here's a paper about something that every college student knows about and which is yet not considered by people who do drug design as often as it should- tautomers. Yvonne Martin (previously at Abbott) has a nice article about why tautomers are important in drug design and what are the continuing challenges in predicting and understanding them. This should be a good reminder for both experimentalists and theoreticians to consider tautomerism in their projects.So why are tautomers important? ........ Read more »
Martin, Y. (2009) Let’s not forget tautomers. Journal of Computer-Aided Molecular Design. DOI: 10.1007/s10822-009-9303-2
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