Genome-wide characterisation of the binding repertoire of small molecule drugs
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Genome-wide characterisation of the binding repertoire of small molecule drugs Lee Makowski* and Diane J. Rodi Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA *Correspondence to: Tel: þ1 630 252 3917; Fax: þ 1 630 252 3853; E mail: [email protected] Date received (in revised form): 21st August 2003
Abstract Most, if not all, drugs interact with multiple proteins. One or more of these interactions are responsible for carrying out the primary therapeutic effects of the drug. Others are involved in the transport or metabolic processing of the drug or in the mediation of side effects. Still others may be responsible for activities that correspond to alternate therapeutic applications. The potential clinical impact of a drug and its cost of development are affected by the sum of all these interactions. The drug development process includes the identification and characterisation of a drug’s clinically relevant interactions. This characterisation is presently accomplished by a combination of experimental laboratory techniques and clinical trials, with increasing numbers of patient participants. Efficient methods for the identification of all the molecular targets of a drug prior to clinical trials could greatly expedite the drug development process. Combinatorial peptide and cDNA phage display have the potential for achieving a complete characterisation of the binding repertoire of a small molecule. This paper will discuss the current state of phage display technology, as applied to the identification of novel receptors for small molecules, using a successful application with the drug Taxole as an example of the technical and theoretical benefits and pitfalls of this method. Keywords: phage display, drug target, molecular recognition, drug receptor, Taxole, Bcl-2
Introduction The concept of a receptor as the component of an organism with which a chemical agent interacts was based originally on the independent work of Paul Ehrlich and J. N. Langley during the late nineteenth century. Pharmaceutical agents are generally believed to exert their therapeutic effect by binding to a particular protein or nucleic acid target.1 Both natural product and synthetic chemical drugs, however, can and do have multiple macromolecule-binding partners (Table 1),2 – 48 such as metabolic breakdown enzymes (ie cytochrome P450 enzymes), side effect-mediating targets and, in some cases, secondary therapeutic targets (see aspirin and Taxole below as specific examples). Recognition of the binding promiscuity of drug molecules is reflected in the recent assembly of a publicly accessible web-based therapeutic target database.49 For a drug to reach the market, an average input of 14 years and US$359 million is required.50 The assessment of toxicity, side effects and metabolic breakdown pathways consumes a large percentage of this investment.51 – 53 The speed with which a drug passes through the various stages of the drug discovery process can be a critical factor for success. Novel strategies that provide informatio
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