Fragment-to-Lead Medicinal Chemistry Publications in 2021

Walsh, Louise; Erlanson, Daniel A.; Esch, Iwan J. P. de; Jahnke, Wolfgang; Woodhead, Andrew J.; Wren, E.

doi:10.1021/acs.jmedchem.2c01827

Cited by 22 publications

(19 citation statements)

References 69 publications

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“…This raised a wider question about the general prevalence of fragment hits with ≤1 HBDs identified in FBDD campaigns where screening sets are not biased for HBD count. An analysis of the review articles “Fragment-to-Lead Medicinal Chemistry Publications” that summarize successful fragment-to-lead studies published each year from 2015 to 2021 − revealed on average 53% of published, progressable fragments (developed into published lead series) had ≤1 HBDs. Similarly, across our screened targets we observed that 44–80% of the hits from the Biophysics or Kinase Hinge sets possessed ≤1 HBD.…”

Section: Discussionmentioning

confidence: 99%

Design and Evaluation of a Low Hydrogen Bond Donor Count Fragment Screening Set to Aid Hit Generation of PROTACs Intended for Oral Delivery

et al. 2023

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The development of orally bioavailable PROTACs presents a significant challenge due to the inflated physicochemical properties of such heterobifunctional molecules. Molecules occupying this "beyond rule of five" space often demonstrate limited oral bioavailability due to the compounding effects of elevated molecular weight and hydrogen bond donor count (among other properties), but it is possible to achieve sufficient oral bioavailability through physicochemical optimization. Herein, we disclose the design and evaluation of a low hydrogen bond donor count (≤1 HBD) fragment screening set to aid hit generation of PROTACs intended for an oral route of delivery. We demonstrate that application of this library can enhance fragment screens against PROTAC proteins of interest and ubiquitin ligases, yielding fragment hits containing ≤1 HBD suitable for optimizing toward orally bioavailable PROTACs.

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Section: Discussionmentioning

confidence: 99%

Design and Evaluation of a Low Hydrogen Bond Donor Count Fragment Screening Set to Aid Hit Generation of PROTACs Intended for Oral Delivery

et al. 2023

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“…In addition to weak interactions with the active site, weakly acidic inhibitors are required to efficiently form interactions with other sites to increase affinity. When small pockets, such as the active site of VE-PTP, are difficult to target via binding affinity, a fragment-based drug discovery (FBDD) approach may be effective. − In FBDD, a low-affinity fragment that binds to a small pocket is used as a starting point for drug lead discovery and is optimized by structure-based drug design (SBDD). This fragment-based approach enables efficient interaction with amino acid residues around the small pocket, making drug discovery possible even in difficult pockets. , The key to successful FBDD is confirmation of sufficient specific binding to the target protein in fragment screening.…”

Section: Introductionmentioning

confidence: 99%

Fragment-Based Discovery of Novel VE-PTP Inhibitors Using Orthogonal Biophysical Techniques

Asano,

Yamanaka,

Ohara

et al. 2023

Biochemistry

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Tyrosine phosphorylation is an essential post-translational modification that regulates various biological events and is implicated in many diseases including cancer and atherosclerosis. Vascular endothelial protein tyrosine phosphatase (VE-PTP), which plays an important role in vascular homeostasis and angiogenesis, is therefore an attractive drug target for these diseases. However, there are still no drugs targeting PTP including VE-PTP. In this paper, we report the discovery of a novel VE-PTP inhibitor, Cpd-2, by fragment-based screening combining various biophysical techniques. Cpd-2 is the first VE-PTP inhibitor with a weakly acidic structure and high selectivity, unlike known strongly acidic inhibitors. We believe that this compound represents a new possibility for the development of bioavailable VE-PTP inhibitors.

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“…Fragment-based drug discovery (FBDD) is a useful method for probing putative drug binding sites and discovering therapeutic lead compounds. − Typically, FBDD involves screening a small library of low molecular-weight compounds against a purified protein target using in vitro biophysical assays. GPCRs remain challenging targets for biophysical screens in FBDD due to their relative instability when removed from a native membrane environment.…”

Section: Introductionmentioning

confidence: 99%

Bioorthogonal Tethering Enhances Drug Fragment Affinity for G Protein-Coupled Receptors in Live Cells

et al. 2023

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G protein-coupled receptors (GPCRs) modulate diverse cellular signaling pathways and are important drug targets. Despite the availability of high-resolution structures, the discovery of allosteric modulators remains challenging due to the dynamic nature of GPCRs in native membranes. We developed a strategy to covalently tether drug fragments adjacent to allosteric sites in GPCRs to enhance their potency and enable fragment-based drug screening in cell-based systems. We employed genetic code expansion to site-specifically introduce noncanonical amino acids with reactive groups in C−C chemokine receptor 5 (CCR5) near an allosteric binding site for the drug maraviroc. We then used molecular dynamics simulations to design heterobifunctional maraviroc analogues consisting of a drug fragment connected by a flexible linker to a reactive moiety capable of undergoing a bioorthogonal coupling reaction. We synthesized a library of these analogues and employed the bioorthogonal inverse electron demand Diels−Alder reaction to couple the analogues to the engineered CCR5 in live cells, which were then assayed using cell-based signaling assays. Tetherable low-affinity maraviroc fragments displayed an increase in potency for CCR5 engineered with reactive unnatural amino acids that were adjacent to the maraviroc binding site. The strategy we describe to tether novel drug fragments to GPCRs should prove useful to probe allosteric or cryptic binding site functionality in fragment-based GPCR-targeted drug discovery.

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Fragment-to-Lead Medicinal Chemistry Publications in 2021

Cited by 22 publications

References 69 publications

Design and Evaluation of a Low Hydrogen Bond Donor Count Fragment Screening Set to Aid Hit Generation of PROTACs Intended for Oral Delivery

Design and Evaluation of a Low Hydrogen Bond Donor Count Fragment Screening Set to Aid Hit Generation of PROTACs Intended for Oral Delivery

Fragment-Based Discovery of Novel VE-PTP Inhibitors Using Orthogonal Biophysical Techniques

Bioorthogonal Tethering Enhances Drug Fragment Affinity for G Protein-Coupled Receptors in Live Cells

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