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Screening synthetic combinatorial libraries, such as mixtures of oligo(N-substituted)glycines, facilitates rapid drug lead discovery and optimization by vastly increasing the number of candidate molecules made and tested. Discovery efficiency and productivity can be further improved by using experimental design to maximize molecular diversity for a given(More)
Screening a diverse, combinatorial library of ca. 5000 synthetic dimer and trimer N-(substituted)glycine "peptides" yielded novel, high-affinity ligands for 7-transmembrane G-protein-coupled receptors. The peptoid library was efficiently assembled using readily available chemical building blocks. The choice of side chains was biased to resemble known(More)
In this chapter we review the use of 3-D pharmacophores in drug discovery. Recent advances are highlighted, including the application of pharmacophore descriptors generated both from ligands and protein binding sites. The application of 3-D pharmacophore fingerprints as molecular descriptors for similarity and diversity applications such as virtual(More)
Combinatorial library design attempts to choose the best set of substituents for a combinatorial synthetic scheme to maximize the chances of finding a useful compound, such as a drug lead. Initial efforts were focused primarily on maximizing diversity, perhaps allowing some bias by the inclusion of a small, fixed set of pharmacophoric substituents. However,(More)
Structure-based virtual screening followed by selection of a top fraction of the rank-ordered result list suffers from many false positives and false negatives because the general scoring functions are not accurate enough. Many approaches have emerged to address this problem by including knowledge about the specific target in the scoring and selection(More)
New approaches for combinatorial library design and molecular diversity analysis have been developed by extending previous work from the fields of quantitative structure-activity relationship, computational chemistry, and chemical information. Recent work has begun to address design efficiency and validation of descriptors for combinatorial library design.
Initial combinatorial library designs were based on 2D substituent properties. Subsequently, two important extensions were introduced to improve the approach: use of pharmacophores to introduce 3D information, and performing calculations on the enumerated library products rather than just on the substituents. Unfortunately, practical compromises due to the(More)
The necessity to generate conformations that sample the entire conformational space accessible to a given molecule is ubiquitous in the field of computer-aided drug design. Protein-ligand docking, 3D database searching, and 3D QSAR are three commonly used techniques that depend critically upon the quality and diversity of the generated conformers. Although(More)
OBJECTIVE The aim of this study was to investigate the effect of chronic heart failure (HF; 16 weeks post left coronary artery ligation) on the brain's orexin (ORX) and related neuropeptide systems. METHODS Indicators of cardiac function, including the percent fractional shortening (%FS) left ventricular posterior wall shortening velocity (LVPWSV) were(More)