Application of combinatorial library methods in cancer research and drug discovery.
Application of combinatorial library methods in cancer research and drug discovery.
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发表时间：
1997-04
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通讯作者：
Kit S. Lam
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作者：
Kit S. Lam
组合化学被认为是药物化学最重要的进展之一。在组合肽文库方法中有五种一般方法：生物文库;空间可寻址的平行固相或溶液相文库;需要去卷积的合成文库方法;“一珠一化合物”文库方法;和使用亲和色谱选择的合成文库方法。除了生物文库方法限于具有真核氨基酸的肽文库之外，所有其他四种合成方法都适用于肽、非肽寡聚体或小分子文库。尽管非肽或小分子文库通常通过合成方法制备，但是使用酶的生物合成方法的最新进展可以使人们能够制备否则难以化学合成的化学文库。在“一珠一化合物”文库方法中，平行筛选文库的每个成员，但必须直接或通过编码策略确定阳性化合物珠的化学结构。成功的组合文库筛选需要可靠的高通量生物测定。固相结合或功能测定以及溶液相测定已成功地用于各种文库方法中。近年来，分子生物学的技术进步和对癌症分子基础的基本理解取得了巨大进展。通过将组合化学和计算化学应用于最近确定的许多癌症靶点，有望在可预见的未来开发出更有效、更特异和毒性更低的抗癌剂。除了作为药物发现的重要工具，组合化学在基础研究中也被证明是无价的。本文简要介绍了组合化学在癌症基础研究和药物发现中的应用。
Combinatorial chemistry is now considered as one of the most important recent advances in medicinal chemistry. There are five general approaches in combinatorial peptide library methods: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the 'one-bead one-compound' library method; and synthetic library methods using affinity chromatography selection. Except for the biological library approach, which is limited to peptide libraries with eukaryotic amino acids, all the other four synthetic approaches are applicable to peptide, non-peptide oligomer or small molecule libraries. Although non-peptide or small molecule libraries are generally prepared by a synthetic approach, recent advances in biosynthetic methods using enzymes may enable one to prepare chemical libraries that are otherwise difficult to synthesize chemically. In the 'one-bead one-compound' library method every member of the library is screened in parallel, but the chemical structure of the positive compound-bead has to be determined either directly or via an encoding strategy. A reliable high-throughput biological assay is needed for a successful combinatorial library screen. Solid-phase binding or functional assays as well as solution phase assays have been used successfully in various library methods. There has been enormous progress in the technological advances of molecular biology and the fundamental understanding of the molecular basis of cancer in recent years. By applying combinatorial chemistry and computational chemistry to the many cancer targets that have recently been identified, it is hopeful that more potent, more specific and less toxic anti-cancer agents will be developed in the foreseeable future. In addition to being a great tool for drug discovery, combinatorial chemistry has also proven to be invaluable in basic research. A few specific examples of the applications of combinatorial chemistry in basic cancer research and drug discovery are described in this mini-review.