Genome-wide characterisation of the binding repertoire of small molecule drugs.
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 Taxoltrade mark as an example of the technical and theoretical benefits and pitfalls of this method.
Makowski
Lee
L
Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA. lmakowski@anl.gov
Rodi
Diane J
DJ
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism*; D001435:Bacteriophages / Q000378:metabolism; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D018390:Gene Targeting; D016678:Genome; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism*; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D019151:Peptide Library; D010455:Peptides; D004364:Pharmaceutical Preparations; D019253:Proto-Oncogene Proteins c-bcl-2; D014404:Tubulin; D017239:Paclitaxel