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I would like clarification on the role of oxygen as a hydrogen bond acceptor in Lipinski's Rule of 5 (for drug absorption). I have learned in my medicinal chemistry class that both electron pairs from an oxygen atoms are able to individually form hydrogen bonds.

I was wondering if every sp3 hybridized oxygen would account for 2 possible hydrogen bond acceptors in this rule for drug absorption? If not, what other mechanisms or in vivo findings are not causing oxygen to not count as double?

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In Advanced Drug Delivery Reviews, 2001, 46, 3-26, (DOI) Lipinski and coworkers write:

Too many hydrogen bond acceptor groups also hinder permeability across a membrane bi-layer. The sum of $\ce{N}$s and $\ce{O}$s is a rough measure of H bond accepting ability.

So, for the empirical rule of five it's simply the number, nothing more.

In the cited article, the situation for amides is addressed on page 19 in the context of log P calculations and correction factors that increase lipophilicity. Here, the authors write:

PRX, a proximity correction factor for nitrogen and oxygen atoms that are close to one another topologically. [...] In addition, for each carboxamide group, we add an extra 1.0 and for each sulfonamide group, we add 2.0

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  • $\begingroup$ This perspective is problematic when focusing amides; the lone pair from the nitrogen interacts more closely with the carbonyl group and is (mostly) unavailable for hydrogen bonding. The some of N's and O's would be inaccurate in the application of this rule. $\endgroup$
    – rocc
    Commented Nov 17, 2016 at 18:19

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