Lead compounds random screening

The availability of medicinal chemistry resources can decide which approach to take in the absence of chemistry, a specific enzyme inhibitor that does not distinguish between host and parasite has little value. If chemistry is available, however, identifying a specific enzyme inhibitor can lead to the discovery of parasite-selective compounds. Random screens that search for novel structures are based on the premise that discovery of a specific inhibitor is an extremely rare event, and so the nutrient-dependent viability format is more desirable for HTS. 

Chemical diversity is a critical variable in drug discovery. To obtain diversity, chemists have turned to natural products, have used random screening of broad chemical collections such as the Fine Chemical Directory and their corporations own chemical directories, and have developed methods of combinatorial chemistry to deliver more compounds. Random screening is performed when there are no starting points—no peptide or natural product leads, and no drugs known to bind to the receptor or enzyme target. 

The discovery that the 4-heteroarylpiperazine-l-carboxyanilide template can generate potent TRPVl antagonists was independently reported by three groups [76-79]. Most of the published work on this class of compounds was carried out by Purdue Pharma, and is focused on the optimization of (13a), a lead compound that had emerged from random screening of a chemical... 

Three approaches may be taken to discover new herbicides. They are (a) the random screening of chemicals, (b) the use of known herbicides as lead compounds for a synthesis program, and (c) the design of compounds interfering with known metabolic processes - the "rational" approach. There are no publications in the field of herbicide discovery that would suggest that the latter approach has advanced very much beyond the theoretical stage. The second approach, sometimes referred to as the "me-too" approach, has both positive and negative features. The... 

Many other non-peptide inhibitors of HIV protease (dihydropyrone, cyclic urea and sulphamide series of compounds) were obtained by modifications of random screening leads. Examples of these include a cyclic sulph-one derivative 147 and 148 (PNU-140690) that showed activity against a variety of HIV t)rpe 1... 

Natural sources are still important sources of lead compounds and new drugs. However, the large diversity of potential natural sources in the world makes the technique of random screening a rather hit or miss process. The screening of local folk remedies (ethnopharmacology) offers the basis of a more systematic approach. In the past this has led to the discovery of many important therapeutic agents, for example, the antimalarial quinine from cinchona bark, the... 

A more random approach to discovering a lead is the combinatorial chemistry approach (see Chapter 6). This uses a simultaneous multiple synthesis technique to produce large numbers of potential leads. These potential leads are subjected to rapid high throughput biological screening to identify the most active lead compounds. Once identified, these lead compounds are subject to further development. 

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