Chance Favors the Prepared Mind - From Serendipity to Rational Drug Design

Kubinyi, Hugo

doi:10.3109/10799899909036635

Cited by 111 publications

(60 citation statements)

References 43 publications

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“…Hugo Kubinyi compiled a list of more than 50 examples where important biological activities of substances were found serendipitously (Kubinyi 1999). In many cases, the substances were intended for quite different uses, and their pharmacological potential surfaced unexpectedly in the course of the studies or was found by accident.…”

Section: Rational Drug Design and Its Limitsmentioning

confidence: 99%

Multi-Level Complexities in Technological Development: Competing Strategies for Drug Discovery

Adam

2010

Science in the Context of Application

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Drug development regularly has to deal with complex circumstances on two levels: the local level of pharmacological intervention on specific target proteins, and the systems level of the effects of pharmacological intervention on the organism. Different development strategies in the recent history of early drug development can be understood as competing attempts at coming to grips with these multi-level complexities. Both rational drug design and high-throughput screening concentrate on the local level, while traditional empirical search strategies as well as recent systems biology approaches focus on the systems level. The analysis of these strategies reveals serious obstacles to integrating the study of interventive and systems complexity in a systematic, methodical way. Due to some fairly general properties of biological networks and the available options for pharmaceutical intervention, drug development is captured in an obstinate methodological dilemma. It is argued that at least in typical cases, drug development therefore remains dependent on coincidence, serendipity or plain luck to bridge the gap between (empirical and/or rational) development methodology and actual therapeutic success. An obstinate dilemma in early drug developmentFor the successful development of technology, it is often crucial to pay close attention to a number of different complex circumstances. Development can be particularly demanding if the complexities lie on different levels of a system. For instance, the design of a technology can require, first, that the technological artifact intervenes in a highly sophisticated way on a specific part of a system. Second, this intervention might have to produce effects in the system as a whole that are mediated by complex systems mechanisms. In such a case, complexities on two levels have to be dealt with: complexity of (local) intervention and complexity of systems effects (or systems complexity).For drug development, both types of complexity play a major role. Pharmaceuticals typically act on target proteins, such as enzymes, receptors or ion channels. The interaction between (potential) drugs and these molecular targets is often highly complex and subject to comprehensive theoretical modeling, chemical design and empirical testing in drug development. This problem is local in nature, being associated with specific proteins and their manipulation by drug molecules. At the same time, the intended and unintended effects of pharmacological interventions lie on the level of entire systems such as cells, organs or the organism

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Section: Rational Drug Design and Its Limitsmentioning

confidence: 99%

Multi-Level Complexities in Technological Development: Competing Strategies for Drug Discovery

Adam

2010

Science in the Context of Application

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“…In some of the reconstructions, initial strategies are depicted as "breadth-first" and then after the discovery as "depth-first" [13], using the idea of problem solving as a search in a tree of instances. A search of the first kind, "breadth-first" is usually useful when we do not have a lot of relevant information about the place (inside the "tree") where the solution is.…”

Section: The "Serendipity Mistake" Reconsidered: Blind Searchmentioning

confidence: 99%

“…Considering the large possible chemistry space, it is common to make a selection of compounds for screening. Among the methods used for this task a kind of "diversity" selection is very common [13] (p 87).…”

Section: The "Rational Turn" In Combinatorial Chemistrymentioning

confidence: 99%

“…By implying an intentional and a planned aspect, this design notion has an obvious rational meaning. One of the most cited examples of the design notion used by the "rational turn" is structure-based drug design [21], in which combinatorial methods for modifying and improving drug leads are used: "structure-based drug design is supported by computer programs for the automated superposition (alignment) of molecules, for flexible docking of ligands and for de novo design of ligands that fit a binding site in shape and complementarity of their physicochemical properties" [13] (p. 9)…”

Section: The "Rational Turn" In Combinatorial Chemistrymentioning

confidence: 99%

“…Kubinyi has also said that "whereas the very first syntheses of huge libraries of peptides, peptide derivatives, peptoids, and other peptidomimetics more or less followed Swift's principle of a random combination of building blocks, the design of focused libraries is now in the foreground" [13].…”

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confidence: 99%

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Discovery by serendipity: a new context for an old riddle

García

2008

Found Chem

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Abstract. 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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Chemoinformatics

Villar¹

2002

Kirk-Othmer Encyclopedia of Chemical Technology

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Chemoinformatics is the intersection between chemistry and information technologies. This discipline has gained importance most noticeably in the agrochemical and pharmaceutical industries, but its presence is felt through all chemistry‐based research and development organizations. This article presents summary of a field that is evolving rapidly and covers the storage, retrieval, and presentation of chemical information, with a brief view of its economic impact. For chemical storage, we describe the two most widely used computer readable chemical notations; SMILES and MOL files. Retrieval of chemical information covers a wide range of multiple aspects that range from simple searches, to virtual screening, pharmacophore‐based searches, and molecular diversity issues. Some aspects of software that allow analysis and presentation of chemical data is also introduced, as well as databases and sources for chemical information.

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Chance Favors the Prepared Mind - From Serendipity to Rational Drug Design

Cited by 111 publications

References 43 publications

Multi-Level Complexities in Technological Development: Competing Strategies for Drug Discovery

Multi-Level Complexities in Technological Development: Competing Strategies for Drug Discovery

Discovery by serendipity: a new context for an old riddle

Chemoinformatics

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