This
article summarizes the evolution of the screening deck at the Novartis
Institutes for BioMedical Research (NIBR). Historically, the screening
deck was an assembly of all available compounds. In 2015, we designed
a first deck to facilitate access to diverse subsets with optimized
properties. We allocated the compounds as plated subsets on a 2D grid
with property based ranking in one dimension and increasing structural
redundancy in the other. The learnings from the 2015 screening deck
were applied to the design of a next generation in 2019. We found
that using traditional leadlikeness criteria (mainly MW, clogP) reduces
the hit rates of attractive chemical starting points in subset screening.
Consequently, the 2019 deck relies on solubility and permeability
to select preferred compounds. The 2019 design also uses NIBR’s
experimental assay data and inferred biological activity profiles
in addition to structural diversity to define redundancy across the
compound sets.
Chemogenetic libraries, collections of well-defined chemical probes, provide tremendous value to biomedical research but require substantial effort to ensure diversity as well as quality of the contents. We have assembled a chemogenetic library by data mining and crowdsourcing institutional expertise. We are sharing our approach, lessons learned, and disclosing our current collection of 4,185 compounds with their primary annotated gene targets (https://github.com/Novartis/MoaBox). This physical collection is regularly updated and used broadly both within Novartis and in collaboration with external partners. ll
A full account on a total synthesis of GPI anchor 1 employing butanediacetal (BDA) groups and a chiral bis(dihydropyran) is presented. The reactivity of selenium and thio glycosides was tuned by the use of BDA groups. This allowed the assembly of an appropriately protected GPI anchor precursor 2 in just six steps from the six building blocks 5 ± 10 including only one protecting group manipulation (see Scheme 1). myo-Inositol was desymmetrised with the bis(dihydropyran) derivative 15 and appropriately protected to give inositol acceptor 21 in nine steps and 17 % overall yield (see Scheme 3). The use of common starting materials and BDA-protections give efficient access to building blocks 5, 6, 7 and 8 (see Scheme 5). A new and improved synthesis of the glucosamine donor 28 is included. In summary, a highly convergent and efficient synthesis of GPI anchor 1, which is clearly adaptable to other GPI anchors, has been reported.
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