Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes

Sandgren, Veronica; Agback, Tatiana; Johansson, Per-Ola; Lindberg, Jimmy; Kvarnström, Ingemar; Samuelsson, Bertil; Belda, Oscar; Dahlgren, Anna

doi:10.1016/j.bmc.2012.05.039

Cited by 26 publications

(25 citation statements)

References 27 publications

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“…The alignment of these structures showed a reasonable conserved three-dimensional structure, except for two amino acids: (a) the conformation of ARG235 in the structure 3DV1 [30] clashes with the ligands from structures 2VIJ [26], 2VJ7 [31], 2VNM [32], 3K5C [16] and 4DPF [33], whereas other equivalent arginines, e.g. ARG296 in the structure 2VIJ [26], show no clashes; (b) the conformation of GLN73 in the structure 3DV1 [30], like most equivalent glutamines in this position, clashes with all ligands except those from the 3K5C [16], 3K5F [34] and 3IVH [35] structures.…”

Section: Preliminary Dockingmentioning

confidence: 99%

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

Elisée

Gapsys

Mele

et al. 2019

J Comput Aided Mol Des

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Using the D3R Grand Challenge 4 dataset containing Beta-secretase 1 (BACE) and Cathepsin S (CatS) inhibitors, we have evaluated the performance of our in-house docking workflow that involves in the first step the selection of the most suitable docking software for the system of interest based on structural and functional information available in public databases, followed by the docking of the dataset to predict the binding modes and ranking of ligands. The macrocyclic nature of the BACE ligands brought additional challenges, which were dealt with by a careful preparation of the three-dimensional input structures for ligands. This provided top-performing predictions for BACE, in contrast with CatS, where the predictions in the absence of guiding constraints provided poor results. These results highlight the importance of previous structural knowledge that is needed for correct predictions on some challenging targets. After the end of the challenge, we also carried out free energy calculations (i.e. in a non-blinded manner) for CatS using the pmx software and several force fields (AMBER, Charmm). Using knowledge-based starting pose construction allowed reaching remarkable accuracy for the CatS free energy estimates. Interestingly, we show that the use of a consensus result, by averaging the results from different force fields, increases the prediction accuracy.

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Section: Preliminary Dockingmentioning

confidence: 99%

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

Elisée

Gapsys

Mele

et al. 2019

J Comput Aided Mol Des

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“…In the first example, Iqbal et al used this coupling as the cyclization step in the synthesis of constrained tri-or tetra-peptidomimetics with a biaryl linker (Scheme 11.13 illustrates a tripeptidomimetic (112)). 219 Fair to moderate yields were obtained for products containing 16-to 22-membered rings.…”

Section: Buchwald-hartwigmentioning

confidence: 98%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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“…107 Inhibition of beta-secretase (BACE) also proved to be a very fertile arena for the discovery of a number of potent macrocyclic inhibitors (69)(70)(71). [108][109][110][111] Finally, macrocycles such as 72 have demonstrated that a several-fold potency improvement could be realized by the cyclization of linear renin inhibitors. 112 …”

Section: Non-hcv Protease Inhibitorsmentioning

confidence: 99%

Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

Kazmierski

Jarvest

Plattner³

et al. 2014

Macrocycles in Drug Discovery

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Enormous progress has been made towards an all-oral, very highly sustained viral response (considered a cure) treatment of hepatitis C. Key ingredients of these therapies are hepatitis C virus (HCV) protease inhibitors (PIs). The first generation linear and covalent PIs, telaprevir and boceprevir, were discovered through the enzyme substrate-based approach and are being followed by a second generation of non-covalent PIs. Many of these are macrocycles, as exemplified by the recently FDA-approved simeprevir. This chapter will detail the science successfully employed in both the substrate-based and inhibitor macrocyclization approaches. Additionally, as HCV PI C-terminal motifs develop critical contacts with the enzyme catalytic Ser139 and adjacent sites, this chapter discusses the mechanistic and structural details of such interactions for both the reversible covalent ketoamide as well as non-covalent sulfonamide and carboxylic acid moieties. Efforts to explore a cyclic boronate motif in various linear and cyclic HCV PIs in search of both Ser139-specific and opportunistic enzyme–inhibitor interactions are also summarized herein. In addition, key clinical and marketed PIs are described, including extensive references to primary literature. Finally, this chapter briefly covers key macrocyclic inhibitors of HCV RNA-dependent RNA polymerase NS5B and selected non-HCV macrocyclic protease inhibitors in order to provide additional insights into the successful design of macrocyclic drugs.

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Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes

Cited by 26 publications

References 27 publications

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

Performance evaluation of molecular docking and free energy calculations protocols using the D3R Grand Challenge 4 dataset

The Synthesis of Macrocycles for Drug Discovery

Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

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