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Both the papers "Directed evolution: the 'rational' basis for 'irrational' design" by Tobin et al. and "Rational and 'Irrational' Design of Proteins and Their Use in Biotechnology" by Nixon et al. reference the concept of "irrational" drug design, but never formally define it in their text.

Is there a formal definition of what makes a drug design process "irrational"? What is the meaning of the term "irrational" in this context?

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"Irrational" design in these papers refers to combinatorial mutagenesis, which is put forward as the alternative to "rational" protein design.

Rational design involves using existing information about a protein to choose residues to mutate.

From Nixon et al.:

Alteration of function by rational approaches can be achieved through single-point mutation, exchange of elements of secondary structure, exchange of whole domains, or generation of fusion proteins

Whereas irrational design uses random mutations to gain insight into the functional capacity of specific residues or domains, which may then be further manipulated by rational approaches.

From Tobin et al.:

‘Irrational’ protein design using directed evolution methods relying on entirely random mutagenesis techniques has also had its successes, particularly in cases in which sequential rounds of mutagenesis have been pursued.

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According to "Drugs: From Discovery to Approval" by Rick Ng. The "rationality" of drug design refers to whether structure is used to inform the design.

The Irrational approach:

involves empirical observations of the pharmacological effects from screening of many chemical compounds, mainly those from natural products. The active component that gives rise to the observed effects is isolated. The chemical formula is determined, and modifications are made to improve its properties.

Whereas the Rational approach:

Requires three-dimensional knowledge of the target structure involved in the disease. Drugs are designed to interact with this target structure to create a beneficial response.

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