Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
Molecular genetics and drug discovery.
Mol Genet Med; 1:133-67 1991. Unique Identifier : AIDSLINE ICDB/93690249 Venuti MC; Dept. of Bioorganic Chemistry, Genentech, Inc., South San; Francisco, CA
Abstract:
As medicinal chemistry has become a more methodical science, the task of discovering new therapeutic agents that work potently, specifically, and without side effects has become increasingly important and difficult. This science, which once relied almost solely on near-blind synthesis and screening for in vivo effects, is focusing on biochemical mechanisms. The task of optimization of structure-activity relationships has been refined into a process without major unidentified obstacles, but bringing the task of discovering new compounds to a comparable state of maturity remains an unmet challenge. The role of molecular genetics in the process of drug discovery is reviewed under the following headings: therapeutics produced by recombinant DNA technology; site-directed mutagenesis (second-generation protein therapeutics, protein structure-function studies); genetically engineered drug discovery tools (enzymes, receptors, cellular adhesion proteins); and future prospects. Molecular genetics is only beginning to identify new targets for drug action. For example, regulation of inducible or tissue-specific gene expression is an obvious, but untapped, target for pharmacological intervention. Gene expression as a therapeutic target is apparent in the case of HIV-1, where the tat trans-activator protein, one of the HIV-1 gene products, has been demonstrated to regulate expression of the complete genome. The power of molecular genetics to provide unique and valuable tools for drug discovery is only now beginning to be exploited. The prospects for uncovering the molecular etiology of a disease state, or for gaining access to a disease-relevant target enzyme or receptor, already are being realized. Numerous opportunities should be provided by human genome mapping. The application of genetic engineering techniques to biochemical and pharmacological problems will facilitate the discovery of novel therapeutics with potent and selective actions. The extent of the impact that molecular biology will have on the drug discovery process will remain unknown for some time. However, recombinant protein therapeutics, in conjunction with structural biology, computer-assisted molecular modeling, computational analysis, and medicinal chemistry, will help make possible better therapies for those diseases already controllable, and new therapies for diseases never before treatable. (200 Refs)
Keywords: Amino Acid Sequence *Drug Design DNA, Recombinant *Genetic Engineering Molecular Biology Molecular Sequence Data Mutagenesis, Site-Directed Proteins/GENETICS MONOGRAPH 930430
M9340831
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Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.
