In the last years there has been a great improvement in the development of computational methods for combinatorial chemistry applied to drug discovery. This approach to drug discovery is sometimes called a “rational way” to manage a well known phenomenon in chemistry: serendipity discoveries. Traditionally, serendipity discoveries are understood as accidental findings made when the discoverer is in quest for something else. This ‘traditional’ pattern of serendipity appears to be a good characterization of discoveries where “luck” plays a key role. In this sense, some initial failures in combinatorial chemistry are frequently attributed to a naïf appropriation of a “serendipity model” for discovery (a “serendipity mistake”). In this paper we try to evaluate this statement by criticizing its foundations. It will be suggested that the notion of serendipity has different aspects and that the criticism to the first attempts could be understood as a “serendipity mistake.” We will suggest that “serendipity” strategies, a kind of blind search, can be seen sometimes as a “genuine part” of scientific practice. A discussion will ensue about how this characterization can give us a better understanding of some aspects of serendipity discoveries.
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There are some criticisms related to the whole combinatorial approach and not only to the first approach, which is not considered here. For example, Horrobin (2000) has suggested that the “artificial,” or in vitro approach, of combinatorial chemistry did not take into account the complexity of in vivo situation. In combinatorial chemistry the proteins are studied as crystals or in an aqueous solution and not in a lipid membrane (in vivo condition), so some hits could be found through combinatorial chemistry that would not be effective in vivo.
But in Fleming’s own words these previous experiences can be seen as a reason for discarding those samples.
The title of this first article is: “Automated Synthesis of Peptides: solid-phase peptide synthesis, a simple and rapid synthetic method, has now been automated” (Merrifield 1965).
It could be argued also that if we understood the relationship between ‘irrational’ and ‘rational’ assumed by the “rational turn” in combinatorial chemistry as a continuum, then we could only speak about a “less rational” strategy and not about an “irrational” strategy. There is also a more radical version of this criticism. The discussion in combinatorial chemistry is not about rationality but about “effective” or “ineffective,” so the rational turn has to be interpreted in a pragmatic way, not in an “epistemic” way. The common reference to the amount of money invested in those techniques and devices as a relevant parameter supports this last view. Nevertheless, according to the examples, the main point is not about rationality itself: it is about which strategy we are allowed to use and whether or not searching in a ‘blind’ way is a wise choice. It could also be argued that a blind search for drug discovery is a good strategy only if the drugs are distributed in a homogenous way in the space to be searched. This last assumption seems to be false, so a blind search would only be a waste of time. However, we do not suppose that a “blind strategy” could be considered a regular strategy. If there is a relationship between serendipity and creativity, then we have to assume that a blind search is not a common path. Consequentially, we cannot recommend a blind search for normal research, but we can use it as an explanation for some particular and very rare events in science.
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I would like to thank two anonymous referees and especially to the editor for their helpful and thoughtful comments on previous versions of this paper. I would also like to thank FONCYT for the research grant that supported the work of this paper, as well as Secyt (Universidad Nacional de Cordoba).
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García, P. Discovery by serendipity: a new context for an old riddle. Found Chem 11, 33–42 (2009). https://doi.org/10.1007/s10698-008-9061-6
- Combinatorial chemistry