Challenges of Fragment-Based Approaches

Second, there are significant sources of errors in both the force field and continuum dielectric model used to approximate solvation effects. As an example, polarization effects are neglected in force fields based on fixed partial charges. A recent extension of the LIECE model has emphasized the importance of quantum mechanics to capture these effects, in particular for sets of inhibitors vith significant differences in the number of formal charges [114]. 

all docking studies presented in this chapter vere performed with a rigid protein. The rigid protein approximation, vhich is required for efficiency reasons, dramatically restricts the number of favorable poses and results in false negatives. As an example, tv o small molecule inhibitors of the NS3 protease have been identified by docking into a molecular dynamics snapshot, vhich vould not have been possible by using the X-ray structure [97]. 

Availability of programs for fragment-based docking. All of our software packages for docking are available for free at http //www.biochem-caflisch.uzh.ch/download/. 

Congreve, M., Chessari, G., Tisi, D., and Woodhead, A.J. (2008) Recent developments in fragment-based drug discovery. Journal of Medicinal Chemistry, 51 (13), 3661-3680. 

Holmes, D.J., and Pompliano, D.L. (2007) Drugs for bad bugs confronting the challenges of antibacterial discovery. Nature Reviews. Drug Discovery, 6, 29-40. 

---