Design rational drug

While large-scale systematic screening of natural (or synthetic) substances have yielded the bulk of modern pharmaceuticals, the use of more sophisticated knowledge-based approaches to drug discovery are now becoming increasingly routine. 

This rational approach to drug design has been adopted in developing a specific inhibitor of the human cellular enzyme, purine nucleoside phosphorylase (PNP). PNP functions in the purine salvage pathway, catalysing the reversible reaction shown below  

The free purine released can then be used in the biosynthesis of new nucleic acids within the cell. 

A library containing several million beads can be screened in a single afternoon. Furthermore, the library is reusable, as it may be washed in 8 M guanidine hydrochloride and then re-screened using a different probe. This split synthesis approach displays the ability to generate peptide libraries of incredible variety, variety that can be further expanded by incorporation of, for example, D-amino acids or rarely occurring amino acids. 

Overall, therefore, various approaches may be adopted in the quest to discover new drugs. The approach generally adopted in biopharmacentical discovery differs from most other approaches in that biopharmaceuticals are produced naturally in the body. Discovery of a biopharmacentical product, therefore, becomes a function of an increased knowledge of how the body itself functions. After its initial discovery, the physicochemical and biological characteristics of the potential drug can then be studied. 

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The lead discovery process is depicted in Figure 10.4-4 and shows how the different methods are interconnected. A lead structure can be discovered by serendipity. In rational drug design all information available about a target serves to direct... 

Rational Drug Design A. Parrill, M. R. Reddy, Eds., Oxford, Oxford (1999). A. P. Johnson, S. M. Green, Encycl. Comput. Chem. 1, 650 (1998). 

GR Marshall, CD Barry, HE Bosshard, RA Dammkoehler, DA Dunn. The conformational parameter m drug design The active analog approach. ACS Symp Ser 112 205-226, 1979. YC Martin. Overview of concepts and methods in computer-assisted rational drug design. Methods Enzymol 203 587-613, 1991. 

Rational drug design is the ultimate goal of medicinal chemistry. By this is understood the design of medicinal agents on the basis of knowledge of the intimate biochemistry of the disease process. 

This method represents the most common and traditional application of computational tools to rational drug design. From a list of molecules of known activity, one can establish a 3D-pharmacophore hypothesis that is then transformed into a 3D-search query. This query is then used to search a 3D database for structures that fit the hypothesis within a certain tolerance. If the yield of active molecules is significant, then the query can be used to predict activities on novel compounds. In our situation, the enantiophore is built from the superposition of a list of sample molecules, which are all well separated on a given CSR Hence, the common features of this series of molecules can become a good enantiophore hypothesis for the enantiores-olution on this CSR... 

Boyd DB. Rational drug design Controlling the size of the haystack. Modem Drug Discovery, November/December 1998. p. 41-8. 

Dyason JC, Wilson JC, Von Itzstein M. Sialidases Targets for rational drug design. In Bultinck P, De Winter H, Langenaeker W, Tollenaere JP, editors. Computational medicinal chemistry for drug discovery. New York Dekker, 2004. 

Carlsson, A (1999) The discovery of the SSRIs a milestone in neuropsychopharmacology and rational drug design. In Selective Serotonin Reuptake Inhibitors (SSRIs) Past, Present and Future (Ed. Stanford, SC), RG Landes Co., Austin, TX, pp. 1-7. 

Zhan C-G (2006) Modeling Reaction Mechanism of Cocaine Hydrolysis and Rational Drug Design for Therapeutic Treatment of Cocaine Abuse. 4 107-159 Zuccato C, see Gambari R (2007) 9 265-276... 

A topic of actuality is the study of receptor proteins and enzymes for which data bases with crystallographic information are now made available. Computer modelling of the active sites of receptors and enzymes are important tools in rational drug design. Principal components and cluster analysis can be applied to the primary... 

The design of a bioreductive alkylating agent possessing antitumor activity described above validates our approach to rational drug design. Namely, the putative... 

Hoi WGJ. Protein crystallography and computer graphics-toward rational drug design. Angew Chem 1986 25 767-778. 

Janoff, A.S., Lipids, liposomes, and rational drug design, Laboratory Investigation, 1992, 66, 655-658. 

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