Drug Design—Chemistry and Biology

At the crossroads of drug discovery and genomic technologies, which have marked a new epoch in science and medicine for the twenty-first century, exists “drug design”––the very essence of interdisciplinary strategies focused on the generation and optimization of lead compounds that may further advance to become clinical candidates and, ultimately, marketed therapeutic agents. From synthetic small-molecules to natural products, peptides and peptidomimetics, proteins, and nucleic acids, there is no question that drug design captivates our imagination and challenges our abilities to advance potent, selective, effective, and safe-acting therapeutic agents to treat various diseases. After several decades, drug design has successfully emerged due in part to the determination of 3-D structures of specific therapeutic targets: (i) numerous proteas es, (ii) an increasing number of signal transduction proteins and other intracellular proteins (i.e., those regulating metabolism, growth, and differentiation), and (iii) a more recent and growing list of receptors and/or their extracellular ligand-binding domains. Such 3-D structures have been achieved and exploited using X-ray crystallography, NMR spectroscopy, and in silico (computer-based) molecular modeling technologies to advance drug discovery. In this commentary, I will attempt to define contemporary drug design and those technology platforms that significantly impact drug design. In many ways, drug design is an “art” that utilizes key concepts and in silico tools (3D molecular modeling and related computational methods, including both cheminformatics and bioinformatics), integrates both chemistry and biology, and exploits human creativity and knowledge. Perhaps that is why drug design so strongly pervades our scientific fascination and remains so intriguing for the genesis of new therapeutic agents.