A decade of molecular complexity

Molecular complexity is one of the key reasons why fragment-based lead discovery should work. As described in 2001 by Mike Hann and colleagues at GlaxoSmithKline, the idea is that very small, simple molecules are likely to be able to bind to many different sites on many different proteins; think of the water molecule as being an extreme example of this. As molecules become larger and more complex, they are less likely to bind to any given site on a protein, though if they are complementary to a site the potency will be greater. Similarly, more complex molecules are more likely to have a single binding mode than smaller, less-decorated molecules, which could assume multiple orientations at a single site. These intuitive ideas were supported by a simple computational model that suggested that there is an optimum complexity where molecules would be simple enough that they would bind to several different targets (and thus be useful in a screening collection) while still being complex enough to bind in single, defined orientations with sufficient potency to permit detection. Mike Hann and Andrew Leach now have a new paper in Current Opinion in Chemical Biology that analyzes how this idea has weathered the past decade.

A central tenet of the molecular complexity model is that more complex molecules should be less promiscuous (bind to fewer protein targets) than less complex molecules. Although defining complexity is itself complex, the authors summarize a number of studies that examine promiscuity as a function of various molecular properties that could be used as proxies for complexity. Interestingly, many of these studies find that as molecular weight or – especially – lipophilicity increases, promiscuity actually increases, an apparent contradiction of the complexity model. Indeed, Hann and Leach present internal data showing that, for a given molecular weight, promiscuity increases with increasing lipophilicity.

The authors consider several explanations for this, such as the notion that larger, lipophilic molecules may not need to be perfectly complementary to a protein: one portion could bind, while the rest of the molecule remains unbound. One explanation that the authors don’t address but that could account for much of the discrepancy is the validity of the measurements from the studies surveyed. Practical Fragments has previously discussed the issue of aggregation artifacts, which can occur even at nanomolar concentration – well below the 10 micromolar cutoff used in many of the cited studies. Indeed, Brian Shoichet has commented that the majority of hits from HTS screens could be artifacts, and an alarming proportion of "active molecules" in published work are also bogus. Thus, the apparent promiscuity of more lipophilic compounds may reflect merely assay artifacts, not true binding.

In other words, I propose at least two kinds of promiscuity. “Legitimately promiscuous” compounds actually bind to multiple proteins in a one-to-one defined fashion. Perhaps these are rare, in line with the complexity model. “Apparently promiscuous” compounds simply interfere with the assay, whether through aggregation, fluorescence artifacts, or other PAINful mechanisms. Given how many discovery programs get side-tracked by these phenomena, these compounds are likely to vastly outnumber legitimately promiscuous molecules, thus distorting the results of data-mining exercises.

There is plenty more in the paper than can be summarized here, and if this piques your interest Mike Hann will be discussing both molecular complexity as well as molecular obesity at the SLAS webinar series starting next month.