How important are chiral molecules?

On this Halloween night, let’s talk about something that has bugged me for a while. I recently realized that I tend to make contradictory remarks in my discussions with faculty colleagues and students. Most of these polarizing statements come out unintentionally. For example, I often talk about my lab’s interest in chirality. In doing so, I naturally imply and state the importance of asymmetry in drug design. Interestingly, as I switch to discussing some elements of my lab’s joint work with the Structural Genomics Consortium (SGC), I am forced to remember about our recent findings that chiral fragments are underperforming in our search for protein binders. Just to remind you about what we do: we run soaking experiments that are aimed at identifying small molecule fragments that bind to proteins. We literally take cocktails of small molecules, soak protein crystals in them, and occasionally get co-crystals. Peter Brown’s group at SGC is doing some really nice work in this regard. As I already mentioned, we have had comparatively little luck with the so-called “3D fragments”, or molecules that are more complex by virtue of having chiral centers. So tell me why should I, in a scientific discourse, continue to overstate the importance of chiral compounds? I have a contradiction here, ladies and gentlemen.

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Molecular complexity is important, but mainly in process research, at a stage when one needs to prepare large amounts of a known (potentially complex) target. The corresponding molecule has likely emerged from iterative rounds of optimization that have inevitably led to increased molecular weight and structural complexity. On the other hand, the track record of chiral molecules at the discovery stage is not too impressive. What I just mentioned extends beyond fragment screening. In fact, if we go back 12 years, we find an interesting report by Hann and colleagues that suggests that collections enriched in very complex molecules generally have a low chance of individual molecules binding to protein targets. The authors suggest that it is far better to start with less complex molecules and increase the potency by increasing the complexity. These findings are correlated with experimental observations we have recently made in fragment screening (and may publish at an opportune time). For me, the implication is clear: avoid chiral centers and complex structures early on. Those who think that complexity favors discovery are profoundly misled. Here is that thought-provoking Hann paper:

http://pubs.acs.org/doi/abs/10.1021/ci000403i

There is an interesting consortium in the UK, called 3Dfrag (http://www.3dfrag.org), whose stated objective is to exploit complex chiral structures in fragment screening. I would be very interested in seeing publications that are hopefully going to come out of their work in the future. For now, I am not convinced that there is definitive data suggesting that chiral molecules enable discovery. So, let’s turn it down a notch with overzealous statements about asymmetric catalysis. Prove me wrong, though, by all means.

10 thoughts on “How important are chiral molecules?

  1. perhaps chiral molecules are not as good at inducing crystallisation in proteins?
    Is that “important”?
    I guess it depends if your interested in crystallising proteins

  2. Well, if we think about fragment driven drug discovery (or probe discovery), we see that this field offers a demonstrable connection between one’s ability to obtain a crystal and the value of the final molecule (cellular activity). Of course, the ultimate molecule looks very different from the initial hit, but such hits usually arise from collections of small atomatic heterocycles. As I listen to those in industry (who confirm the notion that more complex molecules are less likely to be initial leads), I am interested in a comparative study of chiral vs achiral fragments. I don’t think anyone has properly addressed this yet.

  3. sure, but I think its a little like the connection between my bike and eating. I use the bike to get to the store and buy food, so it is very important.

  4. I remember a physicist complaining that He atom is too hard to calculate because it has one too many electrons. Up to maybe two chiral centers for de novo designed drug is fine, but not more, unless you are doing peptides, antibiotics, nucleotides and other natural product-derived stuff.

    I would recommend that you include few simple chiral building blocks into your fragment based work, but that limit yourself to blocks with just one (or zero) chiral center, and definitely use a cheap racemic stuff for soaking.

    X-ray crystallography co-crystal or HTS hit does not equal a lead. A lead is not a drug candidate. A drug candidate is not a drug, yet. At each of these stages, 9 out of 10 does not make it.

    Bioactive secondary metabolites from microbes, plants, fungi and whatnot are evolutionally optimized, for defense function, etc. Most of them are chiral because that is what nature can make. If you start with a complex natural compound as a lead, the chances are your product will be chiral (and the chemistry complicated). But all things equal, and if you have a choice, as a good engineer developing a prototype (which is what medicinal chemists are), you would want to move in the development from complex to more simple, from laborious to easy-to-make, ideally stuff you can buy from a catalog and assemble in a short sequence.

    Too many papers on “generating complexity” come from people who work on multicomponent or domino reactions. The produced compounds look complicated, generate papers and conference presentations. The PIs look for use and funding and parallel synthesis of compounds for screening collections is obvious default.

    Chiral center in your drug candidate is like a mother in law – sometimes, it will help you, but the life is more joyful when there is none…

  5. Not a med chemist, but I was under the impression that chirality and complexity were for the purpose of specificity and novelty. Simple molecules may bind, but they’re more likely to bind multiple proteins and not be unique enough to patent.

  6. I agree that it is worthwhile to re-examine the importance of incorporating chiral molecules into early screening processes. You hit the nail on the head by bringing in Hann’s molecular complexity argument. Ultimately, it comes down to a numbers game. The challenge with chiral compounds is twofold: 1) increased complexity leads to increased variation among fragments of a given size; and 2) compared to so-called ‘flat’ achiral molecules, the degree of protein-ligand complementarity must be greater to get a hit with chiral compounds. The result of both of these challenges is that for a given set of candidates, you are effectively probing a smaller percentage of the vast chemical space for possible fragments.

    Definitely an interesting approach by the 3Dfrag group. Looks like they are using a fair bit of computation. Do you think this can overcome some of the challenges?

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