Colin R. Groom

The druggable genome

An assessment of the number of molecular targets that represent an opportunity for therapeutic intervention is crucial to the development of post-genomic research strategies within the pharmaceutical industry. Now that we know the size of the human genome, it is interesting to consider just how many molecular targets this opportunity represents. We start from the position that we understand the properties that are required for a good drug, and therefore must be able to understand what makes a good drug target.

Locating interaction sites on proteins: the crystal structure of thermolysin soaked in 2% to 100% isopropanol.

Multiple‐solvent crystal structure determination (MSCS) allows the position and orientation of bound solvent fragments to be identified by determining the structure of protein crystals soaked in organic solvents. We have extended this technique by the determination of high‐resolution crystal structures of thermolysin (TLN), generated from crystals soaked in 2% to 100% isopropanol. The procedure causes only minor changes to the conformation of the protein, and an increasing number of isopropanol interaction sites could be identified as the solvent concentration is increased. Isopropanol occupies all four of the main subsites in the active site, although this was only observed at very high concentrations of isopropanol for three of the four subsites. Analysis of the isopropanol positions shows little correlation with interaction energy computed using a molecular mechanics force field, but the experimentally determined positions of isopropanol are consistent with the structures of known protein‐ligand complexes of TLN. Proteins 1999;37:628–640. ©1999 Wiley‐Liss, Inc.