Fragment hopping, mapping waters in SBDD and Statistics

So the lecture went well and it's now online at http://lanyrd.com/2013/eurocup6/schbhf/ with all the others at EuroCUP at http://lanyrd.com/2013/eurocup6/.  Which as ever was a scientific delight.  It wasn't a large meeting, but good discussions and interactions throughout the three days. I really like to go to conferences and and be prompted to look at things in a new way. I particularly liked Andreas Evers (Sanofi) approach to combining synthetic accessibility with 3D fragment hopping (it’s been recently published in J.Med Chem too at  http://dx.doi.org/ 10.1021/jm400404v ). 

I learnt a lot more about water mapping and how it can inform structure based drug design from Matt Geballe(Openeye) and Jasna Klicic (Boehringer-Ingleheim), and finally Pat Waters (Vertex) exhortation to use the right statistics more in evaluating methods is a subject close to my heart so I just enjoyed his talk, and excellent slides.

Interesting group(s) that increase stability

I am always interested in a functional group that improves metabolic stability of small molecules in med chem (most of publications have been in the area). And so I was intrigued by a small study from Novartis chemists/PK people where they found the cyclopropyl-trifluoromethyl (cp-CF3 {C1(CC1)C(F)(F)F}) was a good replacement for tert-butyl (t-butyl {C(C)(C)C}) - publication here. In a small series of compounds the group increased stability as measured by in-vitro incubation with Rat liver microsomes (RLM) and human liver microsomes (HLM). In one example the increase in stability in RLM was dramatic - worth a go if you what you really need is a tool compound for in-vivo study. The matched pairs of compounds overall showed a reproducible increase in stability (we can recommend converting to log10 to place the data in a linear scale then the fold changes are easier to see). Results correlated to lower clearance in-vivo i.v. dosing. MedChemica's favourite replacement was in there, the iso-butyl nitric (i-bu-CN {C(C)(C)C#N}) and in one matched pair showed an increase in stability too - this group has the advantage of reducing lipophilicity as the same time which may be useful for other properties. The cp-CF3 group is interesting; a CF3 is about the same volume at an iso-propyl so it will be like cp-iPr - however would it be as lipophilic or would the strong pull of the CF3 and Walsh orbit interactions with cp make for an interesting dipole? Do they have measured matched pairs for logD? The group disclosed the synthetic route which involved reaction with diazomethane (I used to make loads of this in my PhD, it is alright to work with but it would put off many. There is an process chemistry route to one of the HIV drugs that so it is possible on scale). I suggest that the reagent to consider making and experimenting with would be (HO)2B-c-Pr-CF3 [C1(CC1)(C(F)(F)F)B(O)O] - a boronic acid of the cyclopropyl. Cyclopropyl boronic acid itself undergoes Susuki reactions really well so I imagine it would. Can you deprotonation Cp-CF3?

Evidence Based Medicinal Chemistry

Giving lectures is a mixed pleasure for me.  Creating a story that is engaging and gets the right messages across takes significant time, especially as I try to avoid “death by bulletpoint” and like to create original graphics. I’ve just finished a lecture for the Openeye EuroCUP meeting (http://www.eyesopen.com/events/eurocup-2013) later this week, where I’m talking on “Towards Evidence Based Medicinal Chemistry via Big Data Analysis”. It’s the antithesis of the sort of “Rule of X” approach, which although performed a great service a decade and a half ago in reducing the number of shear daft compounds that were made, has probably run it’s course as it just doesn’t improve drug hunting enough.

Our approach is akin to that used by the Sky Cycling team’s “aggregation of marginal gains” philosophy. In our case using Matched Pairs based data mining to find the specific changes to make to a molecule that will improve it. The “simple rule approach” gives you things like: “for reducing affinity to the hERG ion channel if you have a base in the molecule, keep the logP down, otherwise, OK”.  Although this is elegant in it’s simplicity, it’s actually not a lot of help.  Simplicity can be a distraction, indeed As Einstein said, "If you want elegance, find a tailor".  Probably another target for me, but not a scientific one. The other more technical reason for not liking the simple rule approaches is based on a beautiful piece of analysis done by Andrew Leach when he was at AstraZeneca and recently published. (Med. Chem. Commun., 2012,3, 528-540 http://dx.doi.org/10.1039/C2MD20010D) where they compared various biological properties of enantiomers of compounds, because enantiomers have the same logP, numbers (and strengths) of hydrogen bonding groups, numbers of aromatic rings, numbers of sp3 centres – all the “simple rule” achiral properties”, and then looked to see how much the enantiomers varied. The enantiomers varied rather a lot – which they shouldn’t do if the drivers of the biological effects were simple achiral properties.  We’re more interested in finding the specific structural changes to a base that might improve it, for example adding an alcohol beta to a basic amine centre or converting a piperidine to a morpholine.

It takes a lot of data and a lot of mining to expose some of these nuggets of knowledge, it’s an area where we have significant experience and are still developing the methods, but we’ve case studies where it’s been paying off. Now, off to EuroCUP.

BioTechs moving into Alderley Park

I'm very pleased to hear the news that three companies have moved into Alderley Park; Blueberry Thera, RedX and Imagen Biotech. AstraZeneca's plan to convert AP into an incubator is starting to pay off - the new reports say the site is called BioHub and will be managed by BioCity Nottingham - there's a brand there.... This is a great boast to the NorthWest and I really hope this keeps on building. Most importantly that the people in the these companies talk, collaborate and innovate together. I heard rumours that there is quite a long list of other companies lining up to move in as well. Good luck to all.

http://www.genengnews.com/gen-news-highlights/az-giving-way-to-early-stage-biopharmas-in-cheshire/81248329/