Macromolecular Modeling Blog ™

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:

Fluorine acts as an hydrogen bond acceptor in a predicted ligand pose

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.

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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

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