FBDD and structural biology

The rise of fragment-based drug discovery has largely depended on the success of structural biology. FBDD began in earnest with NMR techniques in the mid 1990s, soon followed by high-throughput crystallography techniques in the early part of this century. In an article published online in Current Opinion in Structural Biology, Christopher Murray of Astex and Tom Blundell of the University of Cambridge discuss this reliance on structure.

The review describes several cases where structural biology played pivotal roles in advancing fragments to leads or drug candidates. Many have been discussed in Practical Fragments, including AT7519 and AT9283 from Astex, the JAK-2 program from SGX, DG-051 from deCODE, HSP90 inhibitors from Vernalis/Novartis and Evotec, Schering-Plough’s BACE inhibitors, and Plexxikon's indeglitazar.

The researchers also discuss the potential of fragment methods for generating inhibitors of antimicrobial targets, such as enzymes in the organisms that cause tuberculosis and sleeping sickness. In these cases too, structural biology played critical roles.

Structural biology is so important, the authors conclude, that “it is only through the expert use of structure-based drug design that FBDD can be expected to fulfill its promise of delivering candidates with the improved physical properties (lower molecular weight and lipophilicity) which it is hoped will lead to reduced attrition in clinical trials.”

But is dependence on structure truly inevitable? The authors themselves highlight one case in which a new antimicrobial agent with animal efficacy was developed using fragment-based methods in the absence of direct structural information. If this success could be generalized, it would open the potential of fragment methods to a much wider range of practitioners.