Balancing target flexibility and target denaturation in computational fragment-based inhibitor discovery.

ABSTRACT: Accounting for target flexibility and selecting "hot spots" most likely to be able to bind an inhibitor continue to be challenges in the field of structure-based drug design, especially in the case of protein-protein interactions. Computational fragment-based approaches using molecular dynamics (MD) simulations are a promising emerging technology having the potential to address both of these challenges. However, the optimal MD conditions permitting sufficient target flexibility while also avoiding fragment-induced target denaturation remain ambiguous. Using one such technology (Site Identification by Ligand Competitive Saturation, SILCS), conditions were identified to either prevent denaturation or identify and exclude trajectories in which subtle but important denaturation was occurring.

SUBMITTER: Foster TJ 

PROVIDER: S-EPMC3438888 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature