Standard Article

Medicinal Chemistry


  1. David J. Triggle

Published Online: 15 SEP 2006

DOI: 10.1002/3527600906.mcb.200400006

Reviews in Cell Biology and Molecular Medicine

Reviews in Cell Biology and Molecular Medicine

How to Cite

Triggle, D. J. 2006. Medicinal Chemistry. Reviews in Cell Biology and Molecular Medicine. .

Author Information

  1. State University of New York, Buffalo, NY, USA

Publication History

  1. Published Online: 15 SEP 2006


Medicinal chemistry defines one component of a sequence of events in the process of drug discovery and development. The critical steps of lead structure identification and refinement have been, and continue to be, the major contributions of medicinal chemistry to the drug discovery process: medicinal chemistry may be thought of as comprising three stages—a discovery step, an optimization step, and a production step (Fig. 1). Historically, drug development has been associated with biologically active products from natural sources, principally plants, and the development of natural product chemistry. Indeed, some 50% of currently available drugs have their origins, directly or indirectly, in natural products. With the ascendancy of synthetic organic chemistry, emphasis was increasingly placed on the screening of synthesized molecules in a variety of biological test systems that moved progressively from in vivo whole-animal systems to single expressed protein systems and to targets derived from reading of the genome. This approach has acquired increasingly mechanistic underpinnings with the development and quantitation of the receptor concept and the availability of receptor-based assays. The processes of lead structure identification and refinement have become progressively more sophisticated in partnership with developments in molecular and structural biology that have led to the characterization of new potentially drugable targets, the availability of human proteins as research tools with which to study drug–receptor interactions and as biopharmaceuticals, and the availability of three-dimensional structures of human receptors and enzymes with which to perform in silico medicinal chemistry. Finally, the new technologies embodied in high-throughput screening and combinatorial chemistry have led to an extraordinary level of biological activity determination: the translation of this productivity into therapeutically available medicines remains, however, a significant problem.

The genomics era, initiated in 1953 with the publication of the Watson and Crick paper on the structure of DNA, has had a major impact not only on biology but also on other scientific disciplines, including chemistry. The basic themes that govern biology—diversity, replication, evolution, and self-organization—are increasingly major components of medicinal chemistry, in the development of combinatorial chemistry, self-replicating molecules, in vitro evolution of molecules to biological fitness, and the synthesis of molecules around a template.

The elucidation of the human genome, as well as the genomes of other species including many bacteria, was the second major event of the genomics era. From the perspective of drug discovery, the human genome was anticipated to yield an enormous increase in the number of potential drug targets and thus greatly expedite the availability of new drugs. Together with the technologies of combinatorial chemistry and high-throughput screening, the production line for new drugs was anticipated to be faster and more capacious by several orders of magnitude. However, the number of human genes, approximately 30 000 (but still an uncertain number), is relatively small by comparison with the number of genes in other species, suggesting that our complexity arises not from a simple increase in the number of proteins, but rather from an expansion in the complexity of the signaling and regulatory networks. Thus, the number of potential drug targets is likely to be significantly smaller than was originally anticipated: nonetheless, the anticipated number of 1000 to 2000 potential targets is still significantly larger than the number of current targets, estimated at approximately 120 in all. The issue remains, however, as to how many of these new targets will actually be drugable.

Knowledge of the human genome will also lead to the introduction of personalized medicine whereby the drug will be matched more precisely to the patient, thus generating better response, facilitating clinical trial development, and reducing drug withdrawal and related misadventures that are typically due to the reactions with an extremely small percentage of patients, but nonetheless prominent because of the large patient base with many drugs.


  • Combinatorial Chemistry;
  • High-throughput Screening;
  • Ligand;
  • Peptidomimetic;
  • Receptor;
  • Stereoselectivity;
  • Structure–Activity Relationships