Fragment Linking Strategies for Structure-Based Drug Design

Abstract

Fragment-based drug discovery is a strategy widely used both in academia and pharmaceutical companies, to generate smallmolecule 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,

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

“…282 Similarly, fragment-based screening holds promise for development of inhibitors of enzymes with larger active sites, 227,[275][276][277][278][279][280] although there are challenges associated with identification of different fragments which bind simultaneously and also in the elaboration of fragment hits into leads. 274,283 It is important that inhibitors produced by rational design, identified by screening and other approaches are fully characterised to determine if covalent modification of the target is occurring. There are examples of rationally designed racemase inhibitors intended to be reversible which appear to exert their effects by covalent modification of the racemase target.…”

Chemical molecular‐based approach to overcome multidrug resistance in cancer by targeting P‐glycoprotein (P‐gp)

“…Compound 33 ( Figure 9A), initially designed and synthesized by Singh et al, 132 was shown to overcome P-gpmediated MDR in vitro and in vivo by Chen et al 133 Compound 33 is a thiazole-based peptidomimetic ( Figure 9A) designed by combining the fragments-based drug design strategy 134,135 and molecular docking analysis-aided drug design strategy. 132 The in vitro MDR reversal assays indicated that 33 reversed PTX, DOX, and vincristine resistance in P-gp-overexpressing cancer cells (SW620/Ad300 and HEK/ABCB1 cells; Figure 9B).…”

Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence

“…In the last decades, fragment-based drug discovery (FBDD) has been established as an efficient approach for the identification of new biologically active compounds (168)(169)(170)(171)(172). To date, four marketed drugs have been discovered by FBDD (173), including vemurafenib (174), venetoclax (175), erdafitinib (160), and pexidartinib (176), while over 40 fragment-based drug candidates are in different stages of clinical trials (177). In FBDD campaigns, small and less complex compounds, commonly with molecular weight (MW) <300 Da and <20 heavy atoms, are screened against therapeutic targets (178,179).…”