Rational Drug Design

Erice Meetings on crystallography are arguably the best organized, most informative, most enjoyable and the most productive scientific meetings ever held due to the talent and devotion of L. Riva di Sanseverino and P. Spadon. The recent meeting on Experimental and Computational Approaches and Structure Based Drug Design organized by P. Codding (Canada) not only upheld the tradition but may have established a new standard. Among the many fine presentations those of W. Hol, P. Fitzgerald and N. Borkakoti were especially noteworthy.

W. Hol (USA) gave a superb summary of the techniques of macromolecular crystallography. He succinctly outlined the evolution of the techniques of crystal growth, data collection, structure determination,analysis and modeling, contrasting traditional with current techniques. During the quest ion period members of the audience asked him to predict the future. By identifying outstanding challenges including failure thus far to crystallize fusion proteins, inability to adequately screen the huge number of crystallization experiments that robotics can generate, the problem of treating disordered solvent, extending resolution and the modeling of small molecules, he presented challenges to the younger members of the audience. Interdisciplinary endeavors will be the hallmark of the next generation of crystallographers. This will include not only collaborations involving biochemistry but other physical chemical techniques including NMR, neutron and electron diffraction, EXAFS, fiber diffraction, etc. Although Wim noted that some useful drug design has been based upon 3Å data and that 2Å data were adequate to the task, it seems likely that future rational drug design may well benefit from higher resolution data.

P. Fitzgerald's (US) eloquent description of the successful structure based design of an inhibitor of HIV protease that has arrested the progress of the disease in 20 of 22 patients was a high point of the meeting.

The description of the design of an anti-arthritis agent based upon rational analysis of crystallographic data and the latest encouraging animal tests were presented by N. Borkakoti (UK). Dorothy Hodgkin who felt that X-ray crystallographic studies would lead to an understanding of the molecular mechanism of diseases and the design of therapeutics to confront them, suffered from severe arthritis for much of her life. That application of crystallographic methods will contribute to the design of anti-arthritic drugs seems most fitting.