Learn More
The chromatin-associated enzyme PARP1 has previously been suggested to ADP-ribosylate histones, but the specific ADP-ribose acceptor sites have remained enigmatic. Here, we show that PARP1 covalently ADP-ribosylates the amino-terminal histone tails of all core histones. Using biochemical tools and novel electron transfer dissociation mass spectrometric(More)
The linear interaction energy (LIE) method is combined with energy minimization and finite-difference Poisson calculation of electrostatic solvation for the estimation of the absolute free energy of binding. A predictive accuracy of about 1.0 kcal/mol is obtained for 13 and 29 inhibitors of beta-secretase (BACE) and HIV-1 protease (HIV-1 PR), respectively.(More)
Alzheimer's disease, the most common amyloid-associated disorder, accounts for the majority of the dementia diagnosed after the age of 60. The cleavage of the-amyloid precursor protein is initiated by-secretase (BACE-1), a membrane-bound aspartic protease, which has emerged as an important but difficult protein target. Here, an in silico screening approach(More)
UNLABELLED MOTIVATION AND METHOD: Small-molecule inhibitors targeting the adenosine triphosphate (ATP) binding pocket of the catalytic domain of protein kinases have potential to become drugs devoid of (major) side effects, particularly if they bind selectively. Here, the sequences of the 518 human kinases are first mapped onto the structural alignment of(More)
High-throughput docking is a computational tool frequently used to discover small-molecule inhibitors of enzymes or receptors of known three-dimensional structure. Because of the large number of molecules in chemical libraries, automatic procedures to prune multimillion compound collections are useful for high-throughput docking and necessary for in vitro(More)
The linear interaction energy method with continuum electrostatics (LIECE) is evaluated in depth on five kinases. The two multiplicative coefficients for the van der Waals energy and electrostatic free energy are shown to be transferable among different kinases. Moreover, good enrichment factors are obtained for a library of 40375 diverse compounds seeded(More)
A fragment-based docking procedure followed by substructure search were used to identify active-site beta-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC(50) values less than 10 microM were measured in at least one of two different mammalian cell-based assays for 12 of the 72(More)
Fragment-based docking was used to select a conformation for virtual screening from a molecular dynamics trajectory of the West Nile virus nonstructural 3 protease. This conformation was chosen from an ensemble of 100 molecular dynamics snapshots because it optimally accommodates benzene, the most common ring in known drugs, and two positively charged(More)
The tyrosine kinase EphB4 is an attractive target for drug design because of its recognized role in cancer-related angiogenesis. Recently, a series of commercially available xanthine derivatives were identified as micromolar inhibitors of EphB4 by high-throughput fragment-based docking into the ATP-binding site of the kinase domain. Here, we have exploited(More)
We review our computational tools for high-throughput screening by fragment-based docking of large collections of small molecules. Applications to six different enzymes, four proteases, and two protein kinases, are presented. Remarkably, several low-micromolar inhibitors were discovered in each of the high-throughput docking campaigns. Probable reasons for(More)