Metrics (such as ligand efficiency) and rules (such as the
rule of three) seem to be some of the more controversial topics around here. If
you aren’t experiencing metric-fatigue, it’s worth checking out a recent (and free!) “Ask the Experts” feature at Future
Med. Chem., in which four prominent scientists weigh in on the utility of
the rules of five and three.
Monash
University’s Jonathan
Baell (of PAINS fame) notes that, as of early 2013, the original 1997 Lipinski
et. al. rule of five paper (and the 2001 reprint) had been cited more than 4600
times! Baell holds that, of the properties covered by the rules – molecular
weight, lipophilicity, number of hydrogen-bond donors (HBD), and number of
hydrogen-bond acceptors (HBA) – the property lipophilicity is probably the most
important. Although he agrees that rules can be too strictly applied, he also
asks:
What sum value is
represented by the dead-end investment that the world never saw because of
application of a Ro5 mentality?
I think this is a good, often-overlooked point. It is easy
to find examples of drugs that violate the rule of five or programs that were
killed by rule-bound managers with limited vision, but, as GlaxoSmithKline’s
Paul Leeson says, “there is massive unexplored chemical space within the Ro5, which
is available to innovative chemists.” Why not put much of the focus here?
Of course, readers of Practical
Fragments are probably thinking as much about the rule of three as the rule
of five, and one of the main criticisms of that rule, particularly by Pete Kenny, has been the fact that it is not clear how to define hydrogen-bond
acceptors: do you count all nitrogen and oxygen atoms, including for example an
amide –NH? I think the common-sense answer would be no, and Miles Congreve, the
first author on the original rule of three paper, seems to agree. He also notes
that the number of hydrogen bond acceptors seems to be less important in general
than the number of hydrogen bond donors, which is negatively correlated with
solubility, permeability, and bioavailability.
Given last year’s poll on the maximum size of fragments
people allow in their libraries, it looks like most people are already capping
molecular weight well below 300 Da, which skews the other parameters toward rule
of three space. That said, Congreve does warn that commercial fragment
libraries “contain too many compounds that are close to 300 Da, rather than
containing a distribution of compounds in the range of 100 – 300 Da,” a
statement borne out by by Chris Swain’s analyses. Of course, the larger you
get, the more possibilities there are, and the optimal property distribution of
a fragment library is still a matter of debate.
Ultimately I think many people will agree with Leeson, who
says that “there are probably sufficient metrics in the literature today,” and
with Celerino Abad-Zapatero, who notes that “additional rules will not be the
answer in the long run.” On this note I promise no more posts on metrics or
rules – for at least a month!
2 comments:
Dan - nice pickup; one thing I sometimes wonder about with fragments is whether sulfur-containing fragments may be best excluded in initial screening, on the account of sulfur's polarizability allowing attractive interactions with almost anything, possibly leading to misleading stickiness at high concentrations in sulfur-containing fragments. I would be interested in your reader's views.
4600 citations? The way people talk about Ro5 I doubt even that many people even read the bloody paper.
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