Biomedical Engineering Reference
In-Depth Information
2
Biostructure-Based
Drug Design
Flemming S. Jørgensen and Jette S. Kastrup
CONTENTS
2.1 Introduction ........................................................................................................................... 29
2.2 Anti-Inl uenza Drugs ............................................................................................................ 31
2.3 HIV Protease Inhibitors ........................................................................................................ 34
2.4 Membrane Proteins ............................................................................................................... 37
2.5 Fast-Acting Insulins .............................................................................................................. 37
2.6 New Methods ........................................................................................................................ 41
2.7 Conclusion............................................................................................................................. 41
Further Readings.............................................................................................................................. 42
2.1 INTRODUCTION
The idea behind biostructure-based drug design is to utilize the information on shape and properties
of the binding site of a target molecule (e.g., enzyme or receptor) to design compounds, which pos-
sess complementary properties. Thus, biostructure-based drug design requires methods for deter-
mination of the three-dimensional (3D) structure of the target molecules as well as knowledge of
which molecular interactions are important to obtain the desired binding characteristics.
Examples of ligands (drug molecules) binding to proteins are shown in Figure 2.1. The two
ligands have been selected to illustrate different types of molecular interactions between the ligand
and the target protein.
The 3D structure of a target protein can be determined experimentally by methods like x-ray
crystallography and NMR spectroscopy, or predicted by computational methods like homology
modeling (comparative model building). Of 50,000 experimentally determined protein structures
43,000 have been determined by x-ray crystallography (Protein Data Bank, May 2008). An x-ray
crystallographic structure determination requires protein crystals, and irradiation with a high-energy
x-ray source generates a diffraction pattern by the scattering of x-rays from organized molecules in
a continuous arrangement in the crystal. Based on the diffraction pattern, an electron density map
of the protein can be derived and subsequently a molecular model rel ecting the electron density,
the 3D structure, can be determined. Presently, the data collection, data processing, model building,
and rei nement are highly automated and computerized processes. The present limiting factor for
determining the 3D structure of a protein is to get sufi cient amounts of pure and stable protein and
proper diffracting crystals.
It is important to consider the quality of an x-ray structure before using it for biostructure-based
drug design. The resolution is a measure of how detailed the electron density map is and thereby how
accurately the positions of the individual atoms can be determined (Figure 2.2A). Structures based
on electron densities at 1.2 Å resolution are normally referred to as atomic-resolution structures and,
e.g., hydrogen-bonding networks can unambiguously be identii ed. Generally, a resolution of ca. 2 Å
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