Beware molecular obesity

Obesity in humans is a growing problem, and not just aesthetically: the condition may be responsible for millions of premature deaths. In a recent article in Med. Chem. Commun., Mike Hann of GlaxoSmithKline notes that “molecular obesity” is also leading to the untimely demise of far too many drug development programs.

Hann, who is especially known for his work on molecular complexity, defines molecular obesity as the “tendency to build potency into molecules by the inappropriate use of lipohilicity.” This is the result of an unhealthy “addiction” to potency. Hann suggests that since potency is easy to measure it is pursued preferentially to other factors, particularly early in a program. This is all too often achieved by adding mass, much of it lipophilic. The problem is that all this grease decreases solubility and increases the risks of off-target binding and toxic side effects.

Tools such as the Rule of 5 have been developed in part to avoid this problem, and a number of other indices have been introduced more recently. For example, lipophilic ligand efficiency (LLE) is defined as pIC50 – LogP; molecules with an LLE > 5 are likely to be more developable. Other guidelines that Hann mentions and that have been covered here include LELP, number of aromatic rings, and fraction of sp3 hybridized carbon atoms. But this is not to say that metrics will save the day:

The problem with the proliferation of so many “rules” is the trend to slavishly apply them without really understanding their required context for use and subsequent limitations.

Starting a program with the smallest possible lead should in theory lead to smaller drugs, and this is one of the key justifications for fragment-based approaches, though even here it is important that the molecules do not become obese during optimization. One of the themes at the 6th annual FBDD conference was to do a bit of optimization around the fragment itself before growing or linking. On a related note, Rod Hubbard warned in his opening presentation at the conference to “beware the super-sized fragment.” Not only are larger fragments likely to be less complementary to the target, the number of possibilities increases (and thus the coverage of chemical space drops) by roughly ten-fold with each atom added to a fragment.

Hann also argues that potency itself is over-rated: many teams seek single digit nanomolar binders even though approved drugs have average potencies of 20 nM to 200 nM.

The paper is a fun read (and is free after registration too). Also, Hann one-ups Donald Rumsfield’s (in)famous “known knowns, known unknowns, and unknown unknowns” by pointing out that much of this information falls into the category of “unknown knowns”:

Those things that are known but have become unknown, either because we have never learnt them, or forgotten about them, or more dangerously chosen to ignore

This review is an excellent corrective to the first two problems, and a clear warning about the third.