A Combined Bioinformatics and Chemoinformatics Approach for Developing Asymmetric Bivalent AMPA Receptor Positive Allosteric Modulators as Neuroprotective Agents

Chen, Haijun; Wang, Cheng Z.; Ding, Chunyong; Wild, Christopher; Copits, Bryan A.; Swanson, Geoffrey T.; Johnson, Kenneth M.; Zhou, Jia

doi:10.1002/cmdc.201200554

Cited by 26 publications

(26 citation statements)

References 54 publications

(52 reference statements)

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“…Lead compound 1 and compound 12 were docked with the STAT3-SH2 domain (PDB code: 1BG1) [25] and AutoDock Vina 1.1.2, using the method as previously described [18,26,27]. Water molecules within the crystal structure were removed and polar hydrogens were added using AutoDockTools.…”

Section: Methodsmentioning

confidence: 99%

Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3)

Chen

Yang

Ding

et al. 2014

European Journal of Medicinal Chemistry

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In a continuing effort to develop orally bioavailable small-molecule STAT3 inhibitors as potential therapeutic agents for human cancer, a series of novel diversified analogues based on our identified lead compound HJC0149 (1) (5-chloro-N-(1,1-dioxo-1H-1λ6-benzo[b]thiophen-6-yl)-2-hydroxybenzamide, Eur. J. Med. Chem. 2013, 62, 498–507) have been rationally designed, synthesized, and pharmacologically evaluated. Molecular docking studies and biological characterization supported our earlier findings that the O-alkylamino-tethered side chain on the hydroxyl group is an effective and essential structural determinant for improving biological activities and druglike properties of these molecules. Compounds with such modifications exhibited potent antiproliferative effects against breast and pancreatic cancer cell lines with IC50 values from low micromolar to nanomolar range. Among them, the newly discovered STAT3 inhibitor 12 (HJC0416) displayed an intriguing anticancer profile both in vitro and in vivo (i.p. & p.o.). More importantly, HJC0416 is an orally bioavailable anticancer agent as a promising candidate for further development.

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Section: Methodsmentioning

confidence: 99%

Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3)

Chen

Yang

Ding

et al. 2014

European Journal of Medicinal Chemistry

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“…However, numerous co-crystal ligand–protein structures with diverse ligands of the GluA2 isoform of the AMPA receptors are now available following two decades of research on this druggable target. After detailed overlay analysis of these crystal structures, a deconstruction–reconstruction approach was applied to design and synthesize two AMPA receptor PAMs with enhanced potency in vitro and remarkable efficacy in vivo for preventing neuroapoptosis (Figure 4) [35]. The first step of this drug discovery campaign was to deconstruct these known ligands into a small fragment library.…”

Section: Ampa Receptor Positive Allosteric Modulatorsmentioning

confidence: 99%

Evolutions in fragment-based drug design: the deconstruction–reconstruction approach

Chen

Zhou

Wang

et al. 2015

Drug Discovery Today

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100

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Recent advances in the understanding of molecular recognition and protein–ligand interactions have facilitated rapid development of potent and selective ligands for therapeutically relevant targets. Over the past two decades, a variety of useful approaches and emerging techniques have been developed to promote the identification and optimization of leads that have high potential for generating new therapeutic agents. Intriguingly, the innovation of a fragment-based drug design (FBDD) approach has enabled rapid and efficient progress in drug discovery. In this critical review, we focus on the construction of fragment libraries and the advantages and disadvantages of various fragment-based screening (FBS) for constructing such libraries. We also highlight the deconstruction–reconstruction strategy by utilizing privileged fragments of reported ligands.

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“…Workers at the university of Texas and Northwestern Universities have recently described an informatics approach to identify new AMPA modulators resulting in sulphonamides (30,31) which are reported to have micromolar activity [89].…”

Section: Summary Of Recent Journal Developments: Focus On New Chemotypesmentioning

confidence: 99%

AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

2015

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The role of glutamate and its receptors in central nervous system biology and disease has long been of interest to scientists involved in both fundamental research and drug discovery, however the complex pharmacology and lack of highly selective compounds has severely hampered drug discovery efforts in this area. Recent advances in the identification and profiling of positive allosteric modulators of the AMPA receptor offer a potential way forward and the hope of a new treatment for schizophrenia. This article will review recent patent applications published in this area.

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A Combined Bioinformatics and Chemoinformatics Approach for Developing Asymmetric Bivalent AMPA Receptor Positive Allosteric Modulators as Neuroprotective Agents

Cited by 26 publications

References 54 publications

Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3)

Discovery of potent anticancer agent HJC0416, an orally bioavailable small molecule inhibitor of signal transducer and activator of transcription 3 (STAT3)

Evolutions in fragment-based drug design: the deconstruction–reconstruction approach

AMPA Receptor-Positive Allosteric Modulators for the Treatment of Schizophrenia: An Overview of Recent Patent Applications

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