On Drug Design

On Drug Design

"About the blog"

Personal reflections on drug design. Research interest includes combining new technology, informatics and science in innovative ways to tackle the challenging tasks in drug discovery...as well as trying to distinguish science facts from science fiction using the power of computers...something I'll post a text on now and then...usually after having read an interesting book/paper.

Copy More! Copy Better!

Drug DesignPosted by Jonas Boström Wed, November 18, 2015 22:58:21

This was first posted: 05/07/2013 here

In the business literature and in various seminars, conferences and workshops, we are continuously bombarded with the message that originality and new ideas are good, while copied and old ideas are bad or unethical – criminal even. Such stupidity. Such complete and utter idiocy!

It is not true that original ideas are always the best, or that copying is always inferior. On the contrary, history is full of stories where original thinking failed completely, and copies managed to outdo originals. Take Google, for instance. Google got in the game at a stage of massive expansion, and was at the time just one search engine among many others. If you look at Google today, you’ll see a company famous for its many brilliant web-based services, but also a company where the most used ones tend to be copies or developments of things invented elsewhere. When I say that Google have copied en masse, I say it with praise and envy. Google are brilliant because they are amazing copiers! Copying can be a highly successful strategy, even though it might not sound quite as elegant and alluring as being recognized as a great original.

In a (rare) moment of clarity, I thought what would not be better than copying text myself to illustrate the power of copying. In fact, what you just read has been copied, word by word, from the book “Dangerous Ideas” [1], with permission from author Alf Rehn. Alf Rehn is a former professor of innovation and entrepreneurship. Thinkers 50, the listing of the world’s top 50 business thinkers, recently included him on their Guru Radar…and I love his provocative way of writing.

In the book, Alf’s lists eight “commandments” (or 7 since the 8th is a copy of the 7th) on how to copy better. One commandment reads “Sometimes you just need to change contexts…” – think current efforts on rescuing and repurposing drugs? Another one states “Small changes can generate big effects: “Dancing with the Stars is a copy of American Idol, but with famous amateurs dancing. Whoever thought of that little variation is rich today”. The analogy that comes to mind here are “follow-on” drugs. The most famous example of a “follow-on” drug is probably Levitra, which is basically a short nitrogen-walk from the original Viagra. Levitra sells for an enormous amount of money (total sales 2010: $242,446,000) [2], and helps people to a…eh…very natural way of copying.

Viagra vs Levitra

Numerous drugs are “follow-ons”, and small changes can indeed make for important patient benefits. For example, replacing a twice-a-day with a once-a-day pill (Terazosin vs Prazosin [3]), and switching to ‘personalized’ medicines (some people respond well to Prozac but not Zoloft). Even so, the approach is most often mentioned with a negative connotation. “Follow-ons” are generally not considered to be truly innovative, as well as the relentless debate on their legal and financial aspects. In a recent review, we analyzed the DiMasi and Faden data set [4] of “first-in class–follow-on” pairs on the market. As many as 70% (N=74) of the pairs are characterized by minor structural variations [5]. Thus, whereas it is generally accepted that large changes in molecular structure leads to large variations in properties, we tend to take too lightly on the fact that small molecular changes can also generate big effects.

It should not be forgotten that many astonishing scientific advances come from copying the science of Mother Nature itself. Evidently, many drugs are close analogues of native ligands or natural product. So, the design message is the following. Do not be afraid of seeking inspiration from competitor’s patent specifications, we have provided tools for that [6], or from nature. Biology and chemical space is to your advantage, increasing the odds that your optimized compounds will be novel with a significantly different, and improved, profile. And when encountering a medicinal chemistry related problem that you believe is specific to your structural series, take a moment to reflect. Your next candidate drug might be closer than you think, quite possibly only a few atoms away.

Some final words of wisdom from “Dangerous Ideas” [1]:

I’m obviously not encouraging people to flout copyright law, and just as in any other activity, you need to ensure that you’re behaving in a sensible and ethical way when copying. But our reaction to this tends to be exaggerated and overly cautions, and just like no one wants to be queer zero, we’re all afraid of being seen as less than original. There is no shame in copying. On the contrary, it is a necessity. Instead of turning away, we should make copying our friend, create copying cultures in our organizations, and see how this approach can generate both brilliant new ideas and an understanding for the reinvention of wheels. We have nothing to lose but our preconceived notions.

Rock on! [7] Alf

References

  1. Rehn, A. (2011) “Dangerous Ideas: When Provocative Thinking Becomes Your Most Valuable Asset”,http://www.strikingly.com/dangerousideas
  2. http://www.drugs.com/top200.html
  3. Kyncl, J.J. (1986) “Pharmacology of Terazosin” Am. J. Med. 80, 12–19
  4. DiMasi, J.A. and Faden, L.B. (2011) “Competitiveness in follow-on drug R&D: a raceor imitation?”Nat. Rev. Drug Discov. 10, 23–27
  5. Giordanetto, F., Boström, J. and Tyrchan C. (2011) “Follow-on drugs: how far should chemists look?” Drug Discovery Today, 16, 722-732.
  6. Tyrchan, C. Boström, J. Giordanetto, F., Winter and Muresan S. (2012) ”Exploiting structural information in patent specifications for key compound prediction” J. Chem. Inf. Model. 52, 1480–1489.
  7. Personal communication with Alf Rehn.



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