Trial and error discovery

One unfortunate, somewhat unexpected, problem arose during the early stages of combinatorial chemistry development. One general reason for combinatorial chemistry development was that the existing theories had a difficult time to predict which molecules would be active and when they could the process was very slow. It became clear that it was faster to do the experiment than it was to model the experiment, and it gave better results. The faster the process became the more mechanical it became or at least the more mechanical it appeared. Consequently, many people developed the attitude that the approach was not science but was rather strictly Edisonian research or, in other words, just highly developed trial and error discovery. This perception somewhat limited the participation of academic groups in the process. 

Historically, the discovery of one effective herbicide has led quickly to the preparation and screening of a family of imitative chemicals (3). Herbicide developers have traditionally used combinations of experience, art-based approaches, and intuitive appHcations of classical stmcture—activity relationships to imitate, increase, or make more selective the activity of the parent compound. This trial-and-error process depends on the costs and availabiUties of appropriate starting materials, ease of synthesis of usually inactive intermediates, and alterations of parent compound chemical properties by stepwise addition of substituents that have been effective in the development of other pesticides, eg, halogens or substituted amino groups. The reason a particular imitative compound works is seldom understood, and other pesticidal appHcations are not readily predictable. Novices in this traditional, quite random, process requite several years of training and experience in order to function productively. 

Only natural dyes were known until the nineteenth century. By trial and error and probably also by chance, humans learned to extract and use a large variety of dyes of vegetable and animal origin. Dyes were extracted from the roots, trunk bark, and branches of trees, the stems, leaves, flowers, and fruits of plants, the bodies of insects and mollusks, and the eggs of insects. All the dyes obtained from natural sources are rather impure, and hence the accurate reproducibility of colors was almost impossible during antiquity. Still, many of the dyes and dyeing techniques used in antiquity were highly developed and remained in use until the discovery of the synthetic dyes in the middle of the nineteenth century (Colombo 1995 Robinson 1969). 

This should come as no surprise, since the physical behavior of materials is non-linear and unpredictable, especially when materials are formulated or in combination. Two examples will suffice high temperature ceramic superconductors and insulators above their critical temperatures or at non-ideal stoichiometries composite structures may show several times the strength or impact resistance than would be expected from their component materials. Materials discovery will always require a good deal of trial and error, factors that may be mitigated by techniques that permit the simultaneous synthesis of large numbers of materials, followed by rapid or parallel screening for desired properties. 

Some drugs will emit light under specific reaction conditions. The discovery of these direct chemiluminescent reactions has come about through trial and error. Table 3 lists some of these drugs and the method used for analysis. Other drugs that are not themselves chemiluminescent can be easily analyzed using a chemiluminescent system (Table 4). 

The discovery of the rare earth elements provide a long history of almost two hundred years of trial and error in the claims of element discovery starting before the time of Dalton s theory of the atom and determination of atomic weight values, Mendeleev s periodic table, the advent of optical spectroscopy, Bohr s theory of the electronic structure of atoms and Moseley s x-ray detection method for atomic number determination. The fact that the similarity in the chemical properties of the rare earth elements make them especially difficult to chemically isolate led to a situation where many mixtures of elements were being mistaken for elemental species. As a result, atomic weight values were not nearly as useful because the lack of separation meant that additional elements would still be present within an oxide and lead to inaccurate atomic weight values. Very pure rare earth samples did not become a reality until the mid twentieth century. 

Traditionally, lead compounds have been discovered in one of two ways. The hrst is one of trial and error. This is the way many plant and animal products and minerals have been found to be effective in the treatment of some medical disorder. For example, no one knows when the hrst person learned that chewing on the bark of the willow tree [Salix alba) helped relieve pain and reduce fever, but willow bark has been used in many cultures for untold centuries for just that purpose. Today we know that the active ingredient in willow bark is a derivative of salicylic acid (CgH4(OH)COOH), which today is sold commercially as aspirin or one of its analogs. Drug researchers continue to rely heavily on the study of folk medicines—a science known as ethnopharmacology—for the discovery of new plant and animal products that may have medical applications in the modern world. Indeed, scientists have discovered that the medical... 

This expense is a strong motivation for medical researchers to develop a more efficient means of drug discovery than the old trial-and-error method. Rational drug discovery is the name given to techniques that employ the principles of chemistry and physics, or are guided by experimental data, to aid in the search for new drugs. 

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