Fragment-based lead discovery of a novel class of small molecule antagonists of neuropeptide B/W receptor subtype 1 (GPR7)

Moningka, Remond; Romero, F. Anthony; Hastings, Nicholas B.; Wang, Ming; Salvo, Jerry Di; Liu, Ying; Trusca, Dorina; Deng, Qiaoling; Tong, Vincent; Terebetski, Jenna L.; Ball, Richard G.; Ujjainwalla, Feroze

doi:10.1016/j.bmcl.2020.127510

Cited by 9 publications

(5 citation statements)

References 16 publications

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Section: Resultsmentioning

confidence: 99%

“…The 2020 table also contains a GPCR example (entry 20), a study that delivered a negative allosteric modulator of GPR7. Careful fragment library screening, hit exploration, and fragment growing resulted in a lead without using structural information or biophysical screening, i.e., types of data that remain difficult to obtain for GPCR targets …”

Section: Resultsmentioning

confidence: 99%

“…Careful fragment library screening, hit exploration, and fragment growing resulted in a lead without using structural information or biophysical screening, i.e., types of data that remain difficult to obtain for GPCR targets. 31 There are also several reports of FBDD targeting RNA. 48−50 Although these programs have not yet produced leads that fulfill all F2L criteria for table inclusion, there is clearly growing interest in identifying fragments that bind to RNA.…”

Section: ■ Resultsmentioning

confidence: 99%

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Fragment-to-Lead Medicinal Chemistry Publications in 2020

Esch

Erlanson²,

Jahnke

et al. 2021

J. Med. Chem.

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Fragment-based drug discovery (FBDD) continues to evolve and make an impact in the pharmaceutical sciences. We summarize successful fragment-to-lead studies that were published in 2020. Having systematically analyzed annual scientific outputs since 2015, we discuss trends and best practices in terms of fragment libraries, target proteins, screening technologies, hit-optimization strategies, and the properties of hit fragments and the leads resulting from them. As well as the tabulated Fragment-to-Lead (F2L) programs, our 2020 literature review identifies several trends and innovations that promise to further increase the success of FBDD. These include developing structurally novel screening fragments, improving fragment-screening technologies, using new computer-aided design and virtual screening approaches, and combining FBDD with other innovative drug-discovery technologies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

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Fragment-to-Lead Medicinal Chemistry Publications in 2020

Esch

Erlanson²,

Jahnke

et al. 2021

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Virtual screening in conjunction with cell-based high concentration screening of fragments has also been carried out to identify agonists for the adrenergic α 2C receptor . Another study used a drug-fragment library biased toward larger fragments and carried out a cell-based functional screen of GPR7 (neuropeptides B/W receptor type 1) . But overall, high-concentration screening in cells is limited by the solubility of screening compounds and often results in high-false positive hit rates due to off-target effects.…”

Section: Introductionmentioning

confidence: 99%

“…15 Another study used a drug-fragment library biased toward larger fragments and carried out a cellbased functional screen of GPR7 (neuropeptides B/W receptor type 1). 16 But overall, high-concentration screening in cells is limited by the solubility of screening compounds and often results in high-false positive hit rates due to off-target effects.…”

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-based lead discovery of indazole-based compounds as AXL kinase inhibitors

Foo

Sim

et al. 2021

Bioorganic & Medicinal Chemistry

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Fragment-based lead discovery of a novel class of small molecule antagonists of neuropeptide B/W receptor subtype 1 (GPR7)

Cited by 9 publications

References 16 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2020

Fragment-to-Lead Medicinal Chemistry Publications in 2020

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

Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors

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