Fragment Linking Strategies for Structure-Based Drug Design

Journal of Medicinal Chemistry
Alexandre BancetIsabelle Krimm

Abstract

Fragment-based drug discovery is a strategy widely used in both academia and pharmaceutical companies to generate small-molecule protein inhibitors and drug candidates. Among the approaches reported in the literature (growing, linking, and merging), the linking approach theoretically offers the opportunity to rapidly gain in binding energy. Nevertheless, this approach is poorly represented when considering the compounds currently in clinical trials. Here, we report an exhaustive view of the cases published so far in the literature, together with the methods used to identify the two initial fragments either simultaneously or successively. We review the different types of linkers published and discuss how these linkers are designed to obtain the lead compound. Mixing merging and linking methods, where the linker is duplicated from a known inhibitor, appears as an interesting strategy. To reach superadditivity, we propose to grow one of the fragments in order to minimize the distance between the two binders and then link the resulting compounds using flexible alkyl-derived linkers.

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Citations

Nov 18, 2020·European Journal of Medicinal Chemistry·Frauke AntoniGünther Bernhardt
Feb 4, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Marie HoarauSumalee Kamchonwongpaisan
Oct 15, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Abdul-Hamid EmwasMariusz Jaremko
Mar 26, 2021·Journal of Chemical Theory and Computation·Roy González-AlemánFabrice Leclerc
May 8, 2021·Trends in Pharmacological Sciences·Zhi-Zheng WangGuang-Fu Yang
Jun 18, 2021·Frontiers in Immunology·José T Moreira-FilhoCarolina H Andrade
Aug 21, 2021·ACS Medicinal Chemistry Letters·Matthew D Shortridge, Gabriele Varani
Nov 12, 2021·Angewandte Chemie·Cansu KayaAnna K H Hirsch
Dec 21, 2021·Journal of Medicinal Chemistry·Iwan J P de EschLouise Walsh
Jan 15, 2022·Journal of the American Chemical Society·Ashley E ModellParamjit S Arora

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