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

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TitleBalancing target flexibility and target denaturation in computational fragment-based inhibitor discovery.
Publication TypeJournal Article
Year of Publication2012
AuthorsFoster, TJ, Mackerell, AD, Guvench, O
JournalJ Comput Chem
Volume33
Issue23
Pagination1880-91
Date Published2012 Sep 05
ISSN1096-987X
KeywordsBinding Sites, Crystallography, X-Ray, Drug Discovery, Interleukin-2, Ligands, Models, Molecular, Molecular Dynamics Simulation, Protein Denaturation, Software, Structure-Activity Relationship
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. The target system used was the well-characterized protein cytokine IL-2, which is involved in a protein-protein interface and, in its unliganded crystallographic form, lacks surface pockets that can serve as small-molecule binding sites. Nonetheless, small-molecule inhibitors have previously been discovered that bind to two "cryptic" binding sites that emerge only in the presence of ligand binding, highlighting the important role of IL-2 flexibility. Using the above conditions, SILCS with hydrophobic fragments was able to identify both sites based on favorable fragment binding while avoiding IL-2 denaturation. An important additional finding was that acetonitrile, a water-miscible fragment, fails to identify either site yet can induce target denaturation, highlighting the importance of fragment choice.

DOI10.1002/jcc.23026
Alternate JournalJ Comput Chem
PubMed ID22641475
PubMed Central IDPMC3438888
Grant ListR15GM099022 / GM / NIGMS NIH HHS / United States
L60 MD003866 / MD / NIMHD NIH HHS / United States
R15 GM099022 / GM / NIGMS NIH HHS / United States
R01 CA107331 / CA / NCI NIH HHS / United States
CA107331 / CA / NCI NIH HHS / United States
CA120215 / CA / NCI NIH HHS / United States
R01 CA120215 / CA / NCI NIH HHS / United States
P41 RR006009 / RR / NCRR NIH HHS / United States