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One of the early and effective approaches to G-coupled protein receptor target family library design was the analysis of a set of ligands for frequently occurring chemical moieties or substructures. Various methods ranging from frameworks analysis to pharmacophores have been employed to find these so-called target-family-privileged substructures. Although(More)
Two distinct G protein-coupled purinergic receptors, P2Y1 and P2Y12, mediate ADP-driven platelet activation. The clinical effectiveness of P2Y12 blockade is well established. Recent preclinical data suggest that P2Y1 and P2Y12 inhibition provide equivalent antithrombotic efficacy, while targeting P2Y1 has the potential for reduced bleeding liability. In(More)
A novel series of 2-hydroxy-N-arylbenzenesulfonamides were identified to be ATP-citrate lyase (ACL) inhibitors with compound 9 displaying potent in vitro activity (IC(50)=0.13 microM). Chronic oral dosing of compound 9 in high-fat fed mice lowered plasma cholesterol, triglyceride, and glucose, as well as inhibited weight gain.
A number of 4'-O-demethylepipodophyllotoxin derivatives possessing various 4 beta-N-, 4 beta-O- or 4 beta-S-aromatic rings have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results indicated, that for DNA topoisomerase(More)
Ball-and-stick mechanical models, typically associated with chemists, have been helpful in understanding structural problems and the relationship between structure and biologic activity. With progress in computer speed, graphics performance, and software innovation, molecules of biological interest can be subjected to rigorous calculations. Computational(More)
The wealth of information available from the solution of the human genome has dramatically altered the nature of combinatorial library design. While single-target-focused library design remains an important objective, creation of libraries directed toward families of receptors such as GPCRs, kinases, nuclear hormone receptors, and proteases, has replaced(More)
For quite some time, the majority of GPCR models have been based on a single template structure: dark-adapted bovine rhodopsin. The recent solution of β2AR, β1AR and adenosine A(2A) receptor crystal structures has dramatically expanded the GPCR structural landscape and provided many new insights into receptor conformation and ligand binding. They will serve(More)
Diversity has historically played a critical role in the design of combinatorial libraries, screening sets and corporate collections for lead discovery. Large library design dominated the field of lead discovery in the 1990s, with design methods ranging from arbitrary and property-based reagent selection to product-based approaches. Over time, however,(More)
Acknowledgement I would like to thank my thesis advisor, Professor Frederick P. Brooks, Jr., for his full support of the ARM project. In 1976 he already had the idea to the use force-feedback ARM in the molecular docking problems. Dr. Mike Cory and Professor David Richardson were the pioneer users of the prototype system from the beginning. have given(More)