ABSTRACT
As HTS technologies come of age, pharmaceutical companies are focusing increasingly on the quality of their screening collections. Storage conditions and their influence on compound stability and solubility are debated intensely. At Novartis, a strategy was developed that is different to most other companies: (1) compounds unsuitable for storage in solution are excluded by computational methods; (2) compounds are stored at 4 degrees C/20% relative humidity in a DMSO/water mixture to avoid freeze-thaw cycles and water uptake and to allow rapid plate replication; (3) resolubilisation of compounds at regular intervals.
Subject(s)
Drug Industry/organization & administration , Drug Storage , Automation , Drug Stability , Robotics , Solubility , SolutionsABSTRACT
This publication describes processes for the selection of chemical compounds for the building of a high-throughput screening (HTS) collection for drug discovery, using the currently implemented process in the Discovery Technologies Unit of the Novartis Institute for Biomedical Research, Basel Switzerland as reference. More generally, the currently existing compound acquisition models and practices are discussed. Our informatics, chemistry and biology-driven compound selection consists of two steps: 1) The individual compounds are filtered and grouped into three priority classes on the basis of their individual structural properties. Substructure filters are used to eliminate or penalize compounds based on unwanted structural properties. The similarity of the structures to reference ligands of the main proven druggable target families is computed, and drug-similar compounds are prioritized for the following diversity analysis. 2) The compounds are compared to the archive compounds and a diversity analysis is performed. This is done separately for the prioritized, regular and penalized compounds with increasingly stringent dissimilarity criterion. The process includes collecting vendor catalogues and monitoring the availability of samples together with the selection and purchase decision points. The development of a corporate vendor catalogue database is described. In addition to the selection methods on a per single molecule basis, selection criteria for scaffold and combinatorial chemistry projects in collaboration with compound vendors are discussed.
Subject(s)
Drug Design , Drug Evaluation, Preclinical/methods , Computational Biology , Databases, Factual , Structure-Activity RelationshipABSTRACT
This paper compares the effectiveness of similarity measures based on two-dimensional fingerprints and on molecular fields for identifying pairs of bioisosteric molecules in the BIOSTER database. The results suggest that the two types of descriptor are complementary in nature, each finding some bioisosteric pairs that are not found by the other. This conclusion is confirmed by studies of groups of BIOSTER molecules that share the same activity characteristics, and by experiments that involve combining the two types of similarity measure.
ABSTRACT
About 1,200 cumulus oocyte complexes were used in an attempt to investigate the influence in vitro of various biological or synthetic inhibitors on meiosis of bovine oocytes. The biological inhibitor used was a low-molecular protein fraction (OMI) of bovine follicle fluid. N6, O2-dibutyryl-cAMP (0.3-1 mol/l), hypoxanthine (4.0 mol/l), adenosine (0.75 mol/l), and nicotinamide (20.0 mol/l) were the synthetic inhibitors. The OMI-active lyophilisate caused inhibition by 34 percent after 24 hours of culturing. Meiosis was inhibited by 15-28 percent by the synthetic inhibitors. Eight transferable embryos have so far resulted from in vitro fertilisation of oocytes of extracorporal non-ovulatory maturation. Pregnancy was achieved in heifer recipients by tubal transfer.
