Structural biology drug discovery

Figure 6 The iterative drug discovery process integrating structural biology, drug design, synthetic chemistry, biological testing, and additional input from other related research areas.

RNA catalysis has been proposed for use in preparing combinatorial libraries of organic structures for drug discovery [39]. As we learn more about the scope, reactivity, and specificity of RNA as a catalyst for organic reactions, it should be possible to use RNA to create new chemical diversity that parallels that found in biological systems, where proteins are the catalysts in the formation of natural products. 

Figure 10.1. Schematic of the structure-based drug discovery/design process. The figure maps out the iterative steps that make use of X-ray crystallography, molecular modeling, organic synthesis, and biological testing to identify and optimize ligand-protein interactions.

On the basis of these data, epothilones A, B and some congeners have been widely pursued as lead structures for the development of a new generation of non-taxane-derived microtubule stabilizers for cancer treatment [5]. Five representatives of this class are currently undergoing clinical evaluation in humans. This outcome confirms the view that natural products provide a vast pool of potential lead structures for drug discovery. In a very general sense, the strategy that resulted in 12-aza-epothilones could be viewed as the synthesis-based equivalent to the discovery of a new natural product with a specific biological activity. 

Sultams (cyclic sulfonamides), sulfonamides in which the S-N bond is part of a ring, have emerged as privileged structures in drug discovery due to their diverse biological properties [25,26). 

Because of their ease of synthesis and their structural similarity to peptides, many laboratories have used peptoids as the basis for combinatorial drug discovery. Peptoids were among the first non-natural compounds used to establish the basic principles and practical methods of combinatorial discovery [17]. Typically, diverse libraries of relatively short peptoids (< 10 residues) are synthesized by the mix-and-split method and then screened for biological activity. Individual active compounds can then be identified by iterative re-synthesis, sequencing of compounds on individual beads, or indirect deduction by the preparation of positional scanning libraries. 

There are three main contributions that structural methods are making to the drug discovery process—structural biology, structure-based design, and structure-based discovery. 

Congreve M, Murray CW, Blundell TL. Structural biology and drug discovery. Drug Discov Today 2005 13 895-907. 

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