The application of an informative, iterative library design strategy is presented for lead identification and optimization. The computational algorithm underlying informative design systematically uses data from both active and inactive compounds and maximizes the information gained from subsequent design-synthesis-screening cycles. Retrospective analysis of a released dataset of 17 550 compoun...

Insights into the proteome reactivity of electrophiles are crucial for designing activity-based probes for enzymes lacking cognate affinity labels. Here, we show that different classes of carbon electrophiles exhibit markedly distinct amino acid labeling profiles in proteomes, ranging from selective reactivity with cysteine to adducts with several amino acids. These data specify electrophilic c...

The zinc fingers of the HIV-1 nucleocapsid protein, NCp7, are prime targets for antiretroviral therapeutics. Here we show that S-acyl-2-mercaptobenzamide thioester (SAMT) chemotypes inhibit HIV by modifying the NCp7 region of Gag in infected cells, thereby blocking Gag processing and reducing infectivity. The thiol produced by SAMT reaction with NCp7 is acetylated by cellular enzymes to regener...

ferula communis l., subsp. communis, namely giant fennel, has extensively been used in traditional medicine for a wide range of ailments. fresh plant materials, crude extracts and isolated components of f. communis showed a wide spectrum of in vitro and in vivo pharmacological properties including antidiabetic, antimicrobial, antiproliferative, and cytotoxic activities. the present paper, revie...

BRPF1 plays a scaffolding role in transcription. We report on fragment screening by high-throughput docking to the BRPF1 bromodomain which resulted in six chemotypes with very favorable ligand efficiency (0.45-0.50 kcal/mol per non-hydrogen atom). Twenty crystal structures of BRPF1/ligand complexes show structural conservation in the acetyllysine binding site, common binding motifs, and unusual...

Chemical constituents and evolutionally neutral DNA sequences of six samples of Cremanthodium lineare Maxim., collected in the Sichuan Province of China, were studied. Three samples produced furanoeremophilanes and the other three, eremophilan-8-ones. The chemotypes were found to be correlated with DNA sequence types, suggesting that the chemical diversity observed has a genetic origin. Product...

We wanted to discover novel chemotypes for 2 targets which lacked x-ray data, CCK2 and 11beta-HSD1. Our approach was to undertake ligand-based virtual screening using the molecular fields of active compounds as our template to define activity. Our hypothesis was that the field pattern of an active molecule describes its key binding features and molecules with a similar field have a high probabi...