Lead compounds Drug

Profile Founded in 1996, this privately held company is a developer of leading edge supercomputer-based technology for rapid conversion of novel gene sequence information into protein structural information and drug lead compounds. 

Once a screening method has been developed and verified, the process of drug lead discovery can be followed much as it has over the last several decades. In the traditional process, a large number of small molecules are tested with the screening method to determine their efficacies as potential drugs or drug lead compounds. 

Traditional Chinese medicines (TCMs) serve as a major source of a variety of drug lead compounds. In the process of natural products development, bioassay-guided isolation is a rapid and validated method for isolation of compounds with bioactivities. This chapter describes bioassay-guided separation and purification of compounds from the crude extracts of TCMs. Two approaches including size-exclusion chromatography (SEC) and high performance liquid chromatography (HPLC) are described in detail. 

Historically, drug absorption, distribution, metabolism, excretion, and toxicity ADMET) studies in animal models were performed after the identification of a lead compound. In order to avoid costs, nowadays pharmaceutical companies evaluate the ADMET profiles of potential leads at an earlier stage of the development... 

Once a number of lead compounds have been found, computational and laboratory techniques are very successful in rehning the molecular structures to yield greater drug activity and fewer side elfects. This is done both in the laboratory and computationally by examining the molecular structures to determine which aspects are responsible for both the drug activity and the side effects. These are the QSAR techniques described in Chapter 30. Recently, 3D QSAR has become very popular for this type of application. These techniques have been very successful in the rehnement of lead compounds. 

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

Cytochrome P450 enzymes have been the subject of a number of recent reviews in which their mechanism and scope of action are covered in much detail [1, 6, 10, 11]. The reader is referred to these articles for a more thorough account of the mechanism and reactivity of cytochrome P450 enzymes, while we present a few representative examples of cytochrome P450-catalyzed epoxidation below. The enzymes we chose are all involved in the biosynthesis of polyketide natural products. Polyketides are a large, structurally diverse family of compounds and have provided a wealth of therapeutically useful drugs and drug leads. 

Incorporating the Kirtas system with the International Plant Names Index and SNOW-MED allows movement of the historic text into an electronic format, identihcation of current plant names, and identihcation of the symptoms treated with the plants. To complete the mining of historic herbal texts for novel drug leads we use the Natural Products Alert (NAPRALERT ) database to compare the information extracted from the historic herbal text to the reports of plant use in the current literature. The NAPRALERT database provides a summary of plants ethnopharmacological use, biochemical activities, and isolated compounds [27]. By querying each plant (with the current plant name) it is possible to identify any reports in the current literature regarding the plant. As an example, Table 4.1 shows the NAPRALERT output for Cycas rumphii. 

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