Dynamic template-assisted strategies in fragment-based drug discovery

Abstract

Fragment-based methods for drug discovery are increasingly popular because they provide drug leads with greater ligand efficiency than conventional high-throughput screening. However, established methods for fragment detection do not address the central question in fragment-based ligand discovery: how can a primary ligand be optimally extended by a secondary fragment? Dynamic screening methods solve this issue by using a protein target as a template for ligand assembly, thus yielding high-affinity binders from low-affinity fragments. This review summarizes recent work on dynamic screening methodology, which resulted in the development of several high-affinity binders for various targets. Strengths and limitations of the published approaches are discussed and possible contributions of dynamic screening methodology to the drug discovery process are highlighted.

Catalytic activation of pre-substrates via dynamic fragment assembly on protein templates

“…F ragment-based development of protein ligands has been recognized over the last years as a powerful strategy to identify molecules with an optimized fit to protein-binding pockets, providing ligands with reduced molecular weight and with higher ligand efficiency, thereby possibly improving the bioavailability, cell permeability and metabolic stability of drug molecules [1][2][3][4][5][6][7][8] . Scrutinizing the chemical space of small molecule fragments-instead of screening large libraries of drug-like molecules-requires considerably smaller chemical libraries for covering the chemical space and thus enables to identify and optimize hit ligands with less effort for testing and chemical synthesis.…”

Kinetic Template‐Guided Tethering of Fragments

“…[45] This protein-directed dynamic combinatorial chemistry (DCC) offers an opportunity to combine synthesis and screening all in one step, in addition to a providing a potential solution to the fragment-linking problem. Furthermore, if one of the components of the mixture is a known binder, the selection of a higher-affinity binding combination is site-directed.…”

Enhanced interrogation: emerging strategies for cell signaling inhibition

“…Success in selectively targeting protein tyrosine phosphatases with such triazole derivatives exemplifies such methodology 34 . The potential for such fragment assembly using dynamic and reversible reactions that can be templated by the target are also being explored 35 . Structure-based approaches have been effective as well in identifying bivalent inhibitors for protein tyrosine phosphatases 36 .…”