Advances in the design of a multipurpose fragment screening library

Abstract

Existing fragment libraries tend to focus on sp (2)-rich compounds covering well-explored areas of chemical space. In order to improve the quality of the hits and to be able to tackle seemingly undruggable targets, flat scaffolds should be replaced by shapely molecular cores dominated by sp (3) hybridization. Structurally novel fragments are needed and in this respect, the role of halogen bonds has been underestimated. Pooling strategies for fragment cocktails must be designed to detect simultaneous binding of weak ligands in close proximity: cooperative binding is too important to rely on chance discoveries.

Functional chromatographic technique for natural product isolation

“…Given the low cost and practical efficacy, we envision that this functional chromatographic method 22 will have utility for lead discovery in general with immediate applications to natural products programs, 22 high-content screening programs, 23 or related fragment-based 24 or natural-product like 25 discovery initiatives. We also see that this tool could be fused directly inline with the steps of these procedures such as natural product isolation or synthetic efforts associated with optimizing small molecule libraries or fragments.…”

Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

“…Starting with in‐house ligand screening, we investigated potential SIRT2 inhibitors with the 2,6,6‐trimethyl‐4‐oxo‐4,5,6,7‐tetrahydro‐1 H ‐indole‐3‐carboxamide scaffold. This partially hydrogenated indole substructure with linked carboxylic acid amides at position 3 is underrepresented in the literature, despite it being an attractive chemical entity in the context of sp 3 ‐rich fragments and hydrophilic substituents. Several amides with the 2,6,6‐trimethyl‐4‐oxo‐4,5,6,7‐tetrahydro‐1 H ‐indole substructure were thus synthesized, characterized and tested for sirtuin inhibitory activity in bioassays.…”

“…Comparing the contents of present diversity‐oriented screening collections with the properties of orally available drugs and natural products, the latter two classes of compounds have more stereocenters and sp 3 ‐hybridized carbon atoms, even when size, in terms of the number of heavy atoms, is accounted for. Thus, biologically relevant compound space might not be ideally populated from a synthetic point of view so far .…”

Tetrazolylhydrazides as Selective Fragment‐Like Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A

“…The combined results encouraged us to select tetrazolyl acetohydrazide 11 a as al ead structuref or the synthesis of derivatives, because its small size resultsi nh igh ligand efficiencies of 0.59 (FDH assay) and 0.78 (LANCE assay), [39] which is av ery good startingp oint for furthers tudies. To generatea rrays of derivativeso f11 a,w ep repared hydrazones 12 a-u with various carbonyl compoundsa iming to increase the binding affinity.D isappointingly,n oneo ft hese derivatives showedi mproveda ctivity,a nd the majority of the synthesized compounds were actually devoid of any activity ( Table 2).…”