In this post, we examine a well-cited study of molecular frameworks in drugs. As defined the frameworks consist of rings joined by linkers and are generated by eliminating atoms in side chains. Frameworks are defined at two levels depending on whether atom and bond types are encoded (atomic) or not (graph). A total of 2505 atomic frameworks were found in a database of 5120 drugs and 1908 (76%) of these are unique (occur only once). A relatively small number (41) of atomic frameworks account for 1235 (24%) of the drugs in the database. A similar analysis was performed for graph frameworks of which there are naturally less and it was found that 32 graph frameworks accounted for half the drugs in the database. However you’ll probably need to convince yourself that differences between piperidine, morpholine, tetrahydropyran, pyrimidine, pyrazine, cyclohexane and benzene are not important if you’re going to find the graph framework analysis useful. Is thiophene more like tetrazole than benzene? Are you feeling lucky?
The primary output of the analysis is a set of frameworks and the frequencies with which they occur in the database. Should you worry if the framework for your active series is only found once in the database? Is it folly to substitute a carboxylate with a tetrazole if that turns a framework that occurs twice in the database into one that has never been seen before? Is a molecule in the drug database because of its framework or in spite of it? Would you prefer a phthalazine to a Penny Black? The difficulty with using results from analyses like this is that we lack a reference point for the observed frequencies.
Readers of this column will be aware that we have reviewed both the Rule of 5. Ro5 is based on analysis of property distributions for a selection of 2245 drugs which have progressed to phase 2 efficacy studies with minimal reference to other compounds. The basis of Ro5 is an appeal to physical chemistry for justification that the chosen properties are indeed relevant to intestinal absorption combined with an assumption that the upper tails of these distributions are unwise places to occupy. We rather liked another study that followed changes in properties of compounds as they progressed thru the development process. That study identified 594 marketed oral drugs. The more observant among you will have noted that 594 and 2245 are significantly smaller numbers than the 5120 drugs in the database for the framework analysis. This raises the question of exactly what was included in the commercial database from which the 5120 drugs were selected.
We were confused by Chart 3. This is claimed to show all six-membered rings found in the drug database. First note the counts for benzene (433) and piperidine (5). Now go back to Chart 2 which shows all atomic frameworks that occur at least 10 times in the drug database. The count for benzene is still 433 so it would appear that Chart 3 actually refers to frameworks not rings. In support of this view we also note that the 4-phenylpiperidine atom framework occurs 12 times, implying that that piperidine is found more commonly linked directly to benzene than as a framework in its own right (see below). We will return to this point in the next post when we review the extension of this analysis to side chains. However at this point we simply note that we just don’t see the point of Chart 3. Perhaps our readers have better ideas and, if so, are encouraged to share them. Were he still alive, Lord Rutherford might have been able help out with a penetrating insight or two. Or a least a set of first day covers from his native New Zealand.
The authors of the analysis suggest that a pharmacological promiscuity parameter could be derived for each framework by dividing the number of targets hit by drugs with the framework by that number of drugs. We are unsure what such a parameter would tell us. Suppose we’re looking at benzene as a framework. In a typical drug, a single benzene ring makes a relatively small contribution to the overall size of the molecule and we would expect the drugs with this framework to be mutually very diverse. The opposite situation will be observed for drugs with large, complex steroid frameworks. Is pharmacological promiscuity defined in this manner a function of the framework or a reflection of variability of non-framework atoms?
This concludes the first part of our review of molecular frameworks. In the next post we will look at side chains. This will be most thrilling and we can barely contain our excitement.
SMILES for Indexing
c1ccccc1
N1CCCCC1
c1ccccc1C2CCNCC2
c1nncc2c1cccc2
2 comments:
Rutherford's Butt. He didn't return his Nobel Prize for (ahem) "Stamp Collecting"...
I have thought a little about how unscientific and brute-force synthesis can be at times, and it's almost a fair cop to say that chemistry has a large projection on the weird/intuitive/black magic axis, especially synthetic work.
Nevertheless, until someone invents stamps that either explode or cure malaria, Ernest Rutherford (whom I admire greatly for his nuclear structure work, and I think his untimely death was a scientific tragedy) can kiss this chemist's ass.
I always wonder what makes physicists so cocky- like somehow having a system that is so simple that you can describe it in a few equations is something to be proud of. Moonshine! Chemistry rules!
Despite what you've said about the black magic in synthesis, it is done in a well developed framework. While physics may have contributed to the development of the framework (e.g. thru molecular orbital methods applied to structure and reactivity), it doesn't define the framework. I would argue that fault for the lack of a strong physical basis lies with the physicists rather than the chemists.
Working in molecular design, I have a very high regard for chemical synthesis. One does not get very far designing molecules if synthetic criteria are ignored. My challenge to the syntheticd world is less natural product synthesis and more unatural product synthesis (I have blogged on this). This does not mean that I am trying to put down synthetic chemistry. I'd just like to see some of that skill channeled more usefully.
One trend in medicinal chemistry is towards data mining. After reading a few articles on druglikeness, the will to live is lost and parallels with stamp collecting become clearer. These analyses is rarely challenged and soon gets cited as fact. Not a problem until your manager reads about it and wants you to implement where you work.
Post a Comment