Balancing target flexibility and target denaturation in computational fragment‐based inhibitor discovery

摘要: Accounting for target flexibility and selecting “hot spots” most likely to be able bind an inhibitor continue challenges in the field of structure-based drug design, especially case protein–protein interactions. Computational fragment-based approaches using molecular dynamics (MD) simulations are a promising emerging technology having potential address both these challenges. However, optimal MD conditions permitting sufficient while also avoiding fragment-induced denaturation remain ambiguous. Using one such (Site Identification by Ligand Competitive Saturation, SILCS), were identified either prevent or identify exclude trajectories which subtle but important was occurring. The system used well-characterized protein cytokine IL-2, is involved interface and, its unliganded crystallographic form, lacks surface pockets that can serve as small-molecule binding sites. Nonetheless, inhibitors have previously been discovered two “cryptic” sites emerge only presence ligand binding, highlighting role IL-2 flexibility. above conditions, SILCS with hydrophobic fragments based on favorable fragment denaturation. An additional finding acetonitrile, water-miscible fragment, fails site yet induce denaturation, importance choice. © 2012 Wiley Periodicals, Inc.