Structure-based drug development

In this chapter we have given an overview of the two major approaches used in NMR and drug discovery, structure-based design and NMR-based screening. Both areas are flourishing and, together with more traditional uses of NMR, they demonstrate the versatility of NMR as a tool in medicinal chemistry. The power of NMR has been dramatically enhanced over the last decade by developments... 

Kubinyi H1998. Structure-based Design of Enzyme Inhibitors and Receptor Ligands. Current Opinion i. Drug Discovery and Development 1 5-15. 

Also in the 1980s, structure-based drug design (SBDD) underwent a similar cycle. Early proponents oversold what could be achieved through SBDD, thereby causing pharmaceutical companies to reconsider their investments when they discovered that SBDD too was no panacea for filling the drug discovery cornucopia with choice molecules for development. Nevertheless, SBDD was an important advance. 

This chapter consists of four main sections. The first provides an overall description of the process of contemporary protein structure determination by X-ray crystallography and summarizes the current computational requirements. This is followed by a summary and examples of the use of structure-based methods in drug discovery. The third section reviews the key developments in computer hardware and computational methods that have supported the development and application of X-ray crystallography over the past forty or so years. The final section outlines the areas in which improved... 

Rutenber E, Fauman EB, Keenan RJ, Ortiz de Montellano PR, Meng E, Kuntz ID, DeCamp DL, Salto R, Rose JR, Craik CS, Stroud RM. Structure of a nonpeptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design. J Biol Chem 1993 268 15343-6... 

All the aforementioned protein members of the cannabinoid system are large, membrane-bound proteins therefore, it is particularly difficult to obtain direct information about their tertiary structure. Thus, at the present time, structure-based drug design is not feasible. Detailed exploration of the SAR and subsequent ligand-based design are the most appropriate means for the development of molecular probes for these proteins. 

Physiologically based pharmacokinetic models provide a format to analyze relationships between model parameters and physicochemical properties for a series of drug analogues. Quantitative structure-pharmacokinetic relationships based on PB-PK model parameters have been pursued [12,13] and may ultimately prove useful in the drug development process. In this venue, such relationships, through predictions of tissue distribution, could expedite drug design and discovery. 

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