ABSTRACT
An important element of any structure-based virtual screening (SVS) technique is the method used to orient the ligands in the target active site. This has been a somewhat overlooked issue in recent SVS validation studies, with the assumption being made that the performance of an algorithm for a given set of orientation sampling settings will be representative for the general behavior of said technique. Here, we analyze five different SVS targets using a variety of sampling paradigms within the DOCK, GOLD and PROMETHEUS programs over a data set of approximately 10,000 noise compounds, combined with data sets containing multiple active compounds. These sets have been broken down by chemotype, with chemotype hit rate used to provide a measure of enrichment with a potentially improved relevance to real world SVS experiments. The variability in enrichment results produced by different sampling paradigms is illustrated, as is the utility of using pharmacophores to constrain sampling to regions that reflect known structural biology. The difference in results when comparing chemotype with compound hit rates is also highlighted.
Subject(s)
Computer Simulation , Drug Design , Ligands , Models, Molecular , Software , Binding Sites , Computational Biology , Computer Graphics , Databases, Protein , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Phosphotransferases (Alcohol Group Acceptor)/physiology , Receptor Protein-Tyrosine Kinases/metabolism , Receptor Protein-Tyrosine Kinases/physiology , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae Proteins/physiology , Serine Endopeptidases/metabolism , Serine Endopeptidases/physiology , Structure-Activity RelationshipABSTRACT
Screening of our in-house compound collection led to the discovery of 5-bromo-6-amino-2-isoquinoline 1 as a weak inhibitor of IMPDH. Subsequent optimization of 1 afforded a series of novel 2-isoquinolinoaminooxazole-based inhibitors, represented by 17, with single-digit nanomolar potency against the enzyme.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Drug Evaluation, Preclinical , Escherichia coli/enzymology , Humans , NAD/metabolism , Structure-Activity RelationshipABSTRACT
A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.
Subject(s)
IMP Dehydrogenase/antagonists & inhibitors , Triazines/chemical synthesis , Triazines/pharmacology , Animals , Cell Division/drug effects , Cells, Cultured , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Molecular Structure , Structure-Activity Relationship , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Triazines/chemistryABSTRACT
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.