When you consider how vast the chemical space is and how restricted the topology and chemical environment of a specific pocket in a protein is, it’s quite surprising we can find molecules that the protein was not evolved to bind that can nonetheless bind and inhibit it potently. It is therefore even more surprising when a single molecule can potently hit two completely unrelated (by sequence, by structure and by function) proteins. Thus, when two independent groups publish such dual kinase/bromodomain inhibitors a week a part from each other, the mind reels.
SCOPE correspondent Suzanne Jacobs writes about the Baker lab’s Computational design of ligand-binding proteins with high affinity and selectivity in Scopeweb | Calculating the Ties that Bind Molecules.
The following reviews provide additional background:
- Emerging themes in the computational design of novel enzymes and protein-protein interfaces.
- An accurate binding interaction model in de novo computational protein design of interactions: If you build it, they will bind.
- Computational design of protein-ligand interfaces: potential in therapeutic development.
Anthony Nicholls (of OpenEye scientific software, Cambridge, MA) recently gave a critical talk on the usage and reporting of Molecular Dynamics simulations. Luckily Ash from The Curious Wavefunction was there to beautifully summarize the main points. I urge you to head over and read the full summary. Below are the main headlines.
- MD is not a useless technique but it’s not held up to the same standards as other techniques, and therefore its true utility is at best unknown
- MD can accomplish in days what other techniques can achieve in seconds or hours
- MD can look and feel “real” and seductive
- Using jargon, movies and the illusion of reality, MD oversells itself to the public and to journals
If you’re interested in protein dynamics and happen to be around the bay area you might want to attend iBAD or “ignite Bay Area protein Dynamics”. Featuring four 5 minute talks by:
- Vijay Pande (Stanford)
- Susan Marqusee (Berkeley)
- Jacob Corn (Genentech)
- Gira Bhabha (UCSF)
When: Nov. 5th 7pm (refreshments available before)
Where: UCSF mission bay campus – Byers Hall 212
See you there.
PAINS or Pan Assay Interference Compounds, are a class of compounds that commonly show up in high throughput screens (HTS) for small molecule inhibitors (you can read more about them here , here and here).
When asked why in his opinion this paper made such an impact, Baell gave an interesting answer: basically it really hit a nerve, and the timing was just right. According to Baell, their group lead some of the first academic HTS efforts, and stumbled upon these PAINS molecules again and again. By the time the paper was published, there were probably dozens of academic labs performing screens and it really resonated with them. Another possible reason for the wide acceptance of this work might have been ex-pharma people, turned academics, who knew these molecules from their past but could not talk about them. Baell mentions for instance that for Chris Lipinski “it was a breath of fresh air…”.
From a practical stand-point you can use this server from the Oprea group to filter your molecules and avoid future PAINS.
The CAPRI 5th evaluation meeting has just finished last week.
Unfortunately I couldn’t attend this year.
Fortunately, you can get the spirit of the meeting from this series of 3 blog posts over at Grid-Cast:
The current CAPRI round is all about peptide docking! Exciting!
If anyone came back from the meeting please share your impressions.
Critical Assessment of Protein Structure Prediction *CASP10* (an EMBO conference)
9-12 December 2012 | Gaeta, Italy
Every two years since 1994 CASP has conducted a community wide experiment to assess the state of the art in protein structure modeling.
The 2012 conference will report the results of 10th experiment and celebrate progress over almost 20 years of monitoring the field.
Recently, as part of a structure based virtual screening campaign I’m undertaking, the following pose popped up as one of the highest ranking solutions:
Wow, that’s a nice looking fluorine-hydrogen bond (C-F···H-X) with that Asparagine, I thought to myself. But wait, can fluorine act as an hydrogen bond acceptor? A quick google scholar search came up with the following (very highly cited) paper: “Organic Fluorine Hardly Ever Accepts Hydrogen Bonds“. In this work Dunitz and Taylor analyze structural data from the PDB and CSD and show that only rarely is fluorine found in appropriate distance to accept a proton: Out of 5947 C-F bonds (in 1218 crystal structures in the CSD), only 37 (0.6%) are involved in possible C-F···H-X hydrogen bonds. For comparison, corresponding figures for C=O and N(Ar) (e.g. in pyridine) groups are 42% and 32%.
What about protein-ligand structures though? It is those that are of most interest to us. Back at the day (1997) Dunitz found only 14 protein-fluorine containing ligand complexes in the PDB and claimed that in these too fluorine rarely acts as an acceptor.
Looking for a more recent analysis, I remembered the very useful “A Medicinal Chemist’s Guide to Molecular Interactions” by Bissantz, Kuhn and Stahl in which they also touch upon halogen hydrogen bonds in protein-ligand complexes. To my surprise however, they take a completely opposite stand on the subject:
“Interactions between CF and polar hydrogen atoms HX (where X = O, N) frequently occur in the PDB and CSD, even if such interactions cannot be classified as strong hydrogen bonds.(ref. to the above Dunitz’s paper) We have observed a thrombin inhibitor to change its binding mode upon fluorination of an aryl ring, such that a CF···HN interaction is formed.(Ref.) In another study on factor VIIa inhibitors, a fluorinated phenyl ring was shown to act as an isostere of a pyridine.(Ref.) An increase of affinity from 455 to 68 nM was observed in sitagliptin analogues binding to DPP-IV when going from 3,4-difluorinated to 2,4,5-trifluorinated triazolopiperazines.(Ref.) The additional ortho-F forms interactions at 3.2 Å distance with NH2 groups of Asn and Arg side chains (PDB code 1×70)”.
Add to this collection of anecdotes a recent pico-molar inhibitor of Cytochrome bc(1) in which a tri-fluro-methyl group contributed a large chunk of affinity and was later shown to make hydrogen bonds in the crystal structure.
So what is the take home message? Does fluorine act a proton acceptor? Is it only in the context of protein-ligand complexes that it is able to form hydrogen bonds? Will you pick a compound predicted to form such an interaction for experimental validation? If you have an opinion vote in the poll below! If you have a reason, explanation or reference please share in the comments.
Jack D. Dunitz, Robin Taylor (1997). Organic Fluorine Hardly Ever Accepts Hydrogen Bonds Chemistry – A European Journal DOI: 10.1002/chem.19970030115
Bissantz C, Kuhn B, & Stahl M (2010). A medicinal chemist’s guide to molecular interactions. Journal of medicinal chemistry, 53 (14), 5061-84 PMID: 20345171