Posts Tagged ‘Derek Lowe’

CH⋅⋅⋅π Interactions between methyl and carbonyl groups in proteins: a small molecule check.

Monday, May 29th, 2017
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Derek Lowe highlights a recent article[1] postulating CH⋅⋅⋅π interactions in proteins. Here I report a quick check using the small molecule crystal structure database (CSD).

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References

  1. F.A. Perras, D. Marion, J. Boisbouvier, D.L. Bryce, and M.J. Plevin, "Observation of CH⋅⋅⋅π Interactions between Methyl and Carbonyl Groups in Proteins", Angewandte Chemie International Edition, vol. 56, pp. 7564-7567, 2017. http://dx.doi.org/10.1002/anie.201702626

Ritonavir: a look at a famous example of conformational polymorphism.

Monday, January 2nd, 2017
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Here is an inside peek at another one of Derek Lowe’s 250 milestones in chemistry, the polymorphism of Ritonavir.[1] The story in a nutshell concerns one of a pharma company’s worst nightmares; a drug which has been successfully brought to market unexpectedly “changes” after a few years on market to a less effective form (or to use the drug term, formulation). This can happen via a phenomenon known as polymorphism, where the crystalline structure of a molecule can have more than one form. In this case, form I was formulated into soluble tablets for oral intake. During later manufacturing, a new less-soluble form appeared and “within weeks this new polymorph began to appear throughout both the bulk drug and formulation areas[1]

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References

  1. J. Bauer, S. Spanton, R. Henry, J. Quick, W. Dziki, W. Porter, and J. Morris, "", Pharmaceutical Research, vol. 18, pp. 859-866, 2001. http://dx.doi.org/10.1023/A:1011052932607

The “hydrogen bond”; its early history.

Saturday, December 31st, 2016
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My holiday reading has been Derek Lowe’s excellent Chemistry Book setting out 250 milestones in chemistry, organised by year. An entry for 1920 entitled hydrogen bonding seemed worth exploring in more detail here.

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How to stop (some) acetals hydrolysing.

Thursday, November 12th, 2015
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Derek Lowe has a recent post entitled "Another Funny-Looking Structure Comes Through". He cites a recent medchem article[1] in which the following acetal sub-structure appears in a promising drug candidate (blue component below). His point is that orally taken drugs have to survive acid (green below) encountered in the stomach, and acetals are famously sensitive to hydrolysis (red below). But if X=NH2, compound "G-5555" is apparently stable to acids.[1] So I pose the question here; why? acetal This reminded me of some work we did a few years ago on herbicides containing such an acetal substructure, where one diastereoisomer was very unstable to hydrolysis (and hence did not have the lifetime required of a herbicide) whereas the other diastereomer was far less labile and hence more suitable.[2],[3] Crystal structures (below) revealed that the two C-O bond lengths of the labile form were very unequal in length (Δ0.043Å), whereas the stable form had two equal C-O lengths (1.408Å, Δ=0.0Å).

Click for 3D

2, but there is one example[cite]10.5517/CC71HVL[/cite],[cite]10.1107/S1600536803006287[/cite] of an orthoformate in which the group equivalent to X is protonated as Me2NH+. For this example, all three C-O lengths are shorter than even the hydrolytically stable herbicide above (1.405, 1.402, 1.396Å). The distribution for 6-ring acetals in general shows hot-spots at ~1.415Å and 1.43Å (but sadly it is not possible to e.g. use this database to correlate these lengths with the aqueous stability of the entries). OCO Is this tentative further evidence that a group X = NH2 positioned as above in an acetal can inhibit its hydrolysis? [caption id="attachment_14757" align="aligncenter" width="400"]HUZKEZ, click for 3D HUZKEZ, click for 3D

Time for calculations. A model (X=R=H) for the hydrolysis was constructed as above in which proton transfer from an acid (ethanoic) is achieved via a cyclic 8-ring transition state and which includes a continuum solvent field as ωB97XD/6-311G(d,p)/SCRF=water and one explicit water in the proton relay. The IRC looks thus: acetalH This shows that the first event is protonation of an oxygen, closely followed by cleavage of the associated C-O bond, and ending with deprotonation of the erstwhile water molecule. acetalha The value of ΔG298 is 38.2 kcal/mol (38.4 in relative total energy). Although rather high for a facile thermal reaction (perhaps the 8-ring TS is a bit too strained; possibly adding a second active water molecule to form a 10-ring might lead to a lower barrier?), we are more interested in the effect upon this barrier of group X (Table below).

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References

  1. C.O. Ndubaku, J.J. Crawford, J. Drobnick, I. Aliagas, D. Campbell, P. Dong, L.M. Dornan, S. Duron, J. Epler, L. Gazzard, C.E. Heise, K.P. Hoeflich, D. Jakubiak, H. La, W. Lee, B. Lin, J.P. Lyssikatos, J. Maksimoska, R. Marmorstein, L.J. Murray, T. O’Brien, A. Oh, S. Ramaswamy, W. Wang, X. Zhao, Y. Zhong, E. Blackwood, and J. Rudolph, "Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pKaPolar Moiety", ACS Medicinal Chemistry Letters, vol. 6, pp. 1241-1246, 2015. http://dx.doi.org/10.1021/acsmedchemlett.5b00398
  2. P. Camilleri, D. Munro, K. Weaver, D.J. Williams, H.S. Rzepa, and A.M.Z. Slawin, "Isoxazolinyldioxepins. Part 1. Structure–reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives", J. Chem. Soc., Perkin Trans. 2, pp. 1265-1269, 1989. http://dx.doi.org/10.1039/P29890001265
  3. P. Camilleri, D. Munro, K. Weaver, D.J. Williams, H.S. Rzepa, and A.M.Z. Slawin, "Isoxazolinyldioxepins. Part 1. Structure–reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives", J. Chem. Soc., Perkin Trans. 2, pp. 1929-1933, 1989. http://dx.doi.org/10.1039/P29890001929

A convincing example of the need for data repositories. FAIR Data.

Thursday, January 15th, 2015
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Derek Lowe in his In the Pipeline blog is famed for spotting unusual claims in the literature and subjecting them to analysis. This one is entitled Odd Structures, Subjected to Powerful Computations. He looks at this image below, and finds the structures represented there might be a mistake, based on his considerable experience of these kinds of molecules. I expect he had a gut feeling within seconds of seeing the diagram.

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