The relative merits of Fragment Based Ligand Design (FBLD) and Diversity-Oriented Synthesis (DOS) were recently debated in a Nature Forum. This debate has already been reviewed both in Practical Fragments and In The Pipeline.
I believe by setting up the debate like this, the editorial staff of the journal show a poor understanding of Lead Discovery (LD). In essence a comparison is being made between apples and oranges. FBLD (also known as FBLG with the LG for lead generation) is an integrated LD framework and a comparison with conventional high throughput screening (HTS) and associated Hit-to-Lead (H2L) chemistry would have made more sense. DOS is essentially an approach to extending the chemical space covered by screening collections and filling ‘holes’ in the existing chemical space. A DOS approach could be easily used to enhance existing fragment libraries (especially if using molecular shape to quantify similarity) while the output of a fragment screen could be used as input to design of DOS libraries. The ‘Core and Layer’ approach that I’ve used in design of generic fragment libraries (and even one library for cell screening) can accurately be described as diversity-oriented.
The case for FBLD is made by Philip Hajduk who makes the important points that a relatively small number of fragments can be used to cover a relatively large chemical space and that synthetic resource is always directed towards the target of interest. I like to say that leads from FBLD are assembled from proven molecular recognition elements and would add that fragments allow you to search chemical space with a better-controlled resolution than do more elaborated molecules. I don’t happen to agree with his assertion that “there is ample evidence that larger molecules are more likely than smaller ones to succeed as drugs in clinical trials” but this does not weaken the first two points that he makes. It's worth remembering that you usually need protein crystal structures in FBLD both for the target (at the outset of screening) and for complexes with weakly-bound fragments. If you don't obtain these quickly you're going to be working on Project Passchendaele.
DOS is championed by Warren Galloway and David Spring. They note that there are situations in which FBLD is not currently applicable, for example in phenotypic screens (see Derek Lowe's comments In The Pipeline) or for probing certain protein-protein interactions. I agree with this point and believe that we’ll always need a variety of assays for successful LD, especially as Drug Discovery is expected to get even more challenging in the future. If you’re trying to enhance the ability of screening libraries to hit targets then it makes sense to use molecular diversity criteria to extend coverage in a more systematic manner. I don’t see why the term DOS should only apply when molecular size exceeds an arbitrary cut off and believe the real issue is more about how than whether DOS should be used to enhance screening libraries.
The advocates of DOS need to take a close look at how they define diversity. If the conserved core of a DOS library cannot be accommodated in a binding site then, barring nuclear fusion, none of the compounds in the library will fit either. From the point of view of this target the library has no diversity regardless of the number of compounds in it.
I was disappointed that molecular complexity (check this link for an alternative view) was not raised by either party in this debate since it’s a unifying concept that brings together different strategies for compound library design. Very complex molecules leave the H2L chemists with little or no room to manoeuvre. This is less of a problem if the screening hit nails the target with nanomolar potency and has jaw-dropping bioavailability. However, reality is more likely to be micromolar with one or more ADMET issues needing to be addressed. Advocates of DOS really do need to start thinking a bit more about molecular complexity in the context of screening compounds for biological activity. I always encourage folk designing a DOS library to make a relatively large sample of the library prototype so that it can be included in the fragment screening collection.
So what’s the verdict? I believe that FBLG is here to stay although it is not yet clear how widely applicable the approach is. I also believe that some form of DOS can be used to enhance any screening collection provided that:
(1) Diversity is seen in the context of the existing collection
(2) The importance of hit exploitability is recognised
I’d be interested to hear what other people think about this topic so feel free to comment. I’ll also set this up as a discussion for the FBDD LinkedIn group since commenting there is a bit easier. Also don’t forget that the journal allows you to comment on the article directly.
Literature cited
Hajduk, Galloway & Spring, A question of library design (Forum Drug Discovery). Nature 2011, 470, 42-43 | DOI
Nicholls et al, Molecular Shape and Medicinal Chemistry: A Perspective. J. Med Chem. 2010, 53, 3862-3886 | DOI
Hann, Leach & Harper, Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery. J. Chem. Inf. Comput. Sci., 2001, 41, 856–864 | DOI
