Discovery combinatorial drug

To speed the process of drug discovery, combinatorial chemistry> has been developed to prepare what are called combinatorial libraries, in which anywhere from a few dozen to several hundred thousand substances are prepared simultaneously. Among the early successes of combinatorial chemistry is the development of a benzodiazepine library, a class of aromatic compounds much used as antianxiety agents. 

Because of their ease of synthesis and their structural similarity to peptides, many laboratories have used peptoids as the basis for combinatorial drug discovery. Peptoids were among the first non-natural compounds used to establish the basic principles and practical methods of combinatorial discovery [17]. Typically, diverse libraries of relatively short peptoids (< 10 residues) are synthesized by the mix-and-split method and then screened for biological activity. Individual active compounds can then be identified by iterative re-synthesis, sequencing of compounds on individual beads, or indirect deduction by the preparation of positional scanning libraries. 

Capitalizing on self-assembly and nanoscience will enhance the ability to screen drugs for individual sensitivities. Advances in drug discovery, combinatorial synthesis, and screening with sensors that have the ability to detect multitudes of specific genetic matches—marrying microelectronics and self-assembly—are expected to be near-term breakthroughs. Then the creation of advanced forms of in the field or in the office tests for chemical risks, pharmaceutical compatibility, or environmental hazards will be possible. 

The identification of compounds with a desired property is a central pursuit in science. In the field of drug discovery combinatorial chemistry has played an increasingly important role for identification and optimization of drug leads which target therapeutically important biomolecules. For the successful implementation of combinatorial methods, new and innovative synthesis methods have been developed. Additionally, novel conceptual approaches to the design of compounds have been pursued to more efficiently generate libraries of small molecules. 

LC/MS is the ultimate analytical technique, which combines the versatility of HPLC with the identification power of MS. The weak link in LC/MS has always been the interface which connects the liquid stream at atmospheric pressure to the high vacuum present inside the mass spectrometer. The development of several atmospheric pressure interfaces, electrospray and atmospheric pressure chemical ionization (APCI), has contributed to the tremendous success and popularity of LC/MS and LC/MS/MS in bioresearch, drug discovery, combinatorial analysis and pharmacokinetic assays. This topic is covered in more depth in a later chapter. 

Burke, T.J., Loniello, K.R., Beebe, J.A. and Ervin, K.M. (2003) Development and application of fluorescence polarization assays in drug discovery. Combinatorial Chemistry High Throughput Screening, 6, 183-194. 

Ecker, D. Crooke, S. (1995). Combinatorial drug discovery which methods will produce greatest value Bio Technology 13, 351-359. 

Beeley, N., Berger, A. (2000) A revolution in drug discovery. Combinatorial chemistry still needs logic to drive science forward. BMJ[Br Med//321(7261), 581-582. 

Lam, K. S. 1997. Application of combinatorial library methods in cancer research and drug discovery. Anticancer Drug Des.,12,145-167. 

Another important aspect of combinatorial drug discovery is chemistry development. It is crucial to discover experimental conditions that ensure high purity and yield of each member of the desired library. Combination of different solid supports, linkers, solvents, temperatures, reagents, etc. can easily lead to multidimensional experiments with hundreds of data points to be collected. Automation is as important for this stage of combinatorial drug discovery as it is for all other aspects. 

Other interesting combinatorial chemistry methods have been developed over the last few years in response to the unmet needs of the pharmaceutical industry. The rising costs of drug discovery and drug development and the slow rate of approval of new chemical entities (NCEs) are at the center of these unmet needs. Combinatorial chemistry may offer the industry faster and cheaper drug discovery paradigms that will increase the rate at which successful compounds reach the patient. 

Keywords. High throughput techniques, Chromatography, Mass spectrometry, Drug discovery Combinatorial chemistry... 

Banks R E et al 2000 Proteomics new perspectives, new biomedical opportunities. Lancet 356 1749-1756 Beeley N, Berger A 2000 A revolution in dmg discovery combinatorial chemistry stiU needs logic to drive science forward. British Medical Journal 321 581-582 Black J W 1986 Pharmacology analysis and exploration. British Medical Journal 293 252 Crystal R G 1995 The gene as a drug. Nature Medicine 1 15... 

Today, it is obvious that in drug discovery combinatorial chemistry cannot displace natural product research. However, natural product chemistry can take advantage of combinatorial strategies. In our opinion, the discovery and development of innovative therapeutic agents will substantially benefit from the... 

Profile Founded in late 1996, SIDDCO is a privately held company that is based on a mission to integrate and apply state-of-the-art approaches to drug discovery. SIDDCO is a combinatorial chemistry consortium that pools the resources of the consortium partners to fund a critical mass of chemists to develop the combinatorial chemistry technology database and methodologies. SIDDCO provides a dedicated team of medicinal chemists to each partner to exploit the shared technology and satisfy the drug discovery and drug optimization needs of specific projects. 

Harold N. Weller, Ph.D. Combinatorial Drug Discovery Department, Bristol-Myers Squibb Co., Princeton, New Jersey... 

Drug discovery, combinatorial, high-throughput screening, proteomics... 

Shi, Y. (2006) Orphan nuclear receptors, excellent targets of drug discovery. Combinatorial Chemistry and High Throughput Screening, 9, 683-689. 

Substructure frequencies of CNS-active drugs provide a good orientation in lead discovery, combinatorial library design, and lead optimization (Eig. 4.18). 

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