Drug Design Targeting Protein–Protein Interactions (PPIs) Using Multiple Ligand Simultaneous Docking (MLSD) and Drug Repositioning: Discovery of Raloxifene and Bazedoxifene as Novel Inhibitors of IL-6/GP130 Interface

Li, Huameng; Xi, Hui; Lin, Li; Jou, David; Kumari, Vandana; Lin, Jiayuh; Li, Chenglong

doi:10.1021/jm401144z

Cited by 131 publications

(130 citation statements)

References 35 publications

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“…A number of BCL-2/BH3 PPI inhibitors such as GX15-070 and AT-101 are used in early clinical trials for a variety of solid tumors, including lung carcinoma and GIST, with more expectation (150, 151). Utilizing a multiple ligand simultaneous docking (MLSD) model, a group has identified raloxifene and bazedoxifene as potent inhibitors of the IL-6/GP130 interface, a critical step in the STAT3-mediated pathway of cancer progression (152). In the context of cerebral ischemia and neuropathic pain, GABAB receptors are often excessively upregulated (153, 154), and small peptides interfering with GABA-interacting proteins such as 14–3–3 may selectively restore normal GABA function without affecting the GABA receptors not implicated in disease (155, 156).…”

Section: Ais Targeting As a Pharmacological Strategymentioning

confidence: 99%

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

2014

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The progress of developing effective interventions against psychiatric disorders has been limited due to a lack of understanding of the underlying cellular and functional mechanisms. Recent research findings focused on exploring novel causes of psychiatric disorders have highlighted the importance of the axonal initial segment (AIS), a highly specialized neuronal structure critical for spike initiation of the action potential. In particular, the role of voltage-gated sodium channels, and their interactions with other protein partners in a tightly regulated macromolecular complex has been emphasized as a key component in the regulation of neuronal excitability. Deficits and excesses of excitability have been linked to the pathogenesis of brain disorders. Identification of the factors and regulatory pathways involved in proper AIS function, or its disruption, can lead to the development of novel interventions that target these mechanistic interactions, increasing treatment efficacy while reducing deleterious off-target effects for psychiatric disorders.

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Section: Ais Targeting As a Pharmacological Strategymentioning

confidence: 99%

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

2014

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“…21,22,66 Homodimerization of the IL-6/IL-6Ra/gp130 heterotrimers triggers phosphorylation of the gp130-associated Janus kinase, and subsequent phosphorylation of tyrosine residues on the intracellular cytoplasmic tail of gp130 generates docking sites for the SH2 domains of STAT3. 21,22,24,66 JAK-mediated phosphorylation of the tyrosine-705 residue of STAT3 recruited to the activated IL-6/IL-6Ra/gp130/JAK complex enables reciprocal interactions between SH2 domains of pSTAT3 monomers to form dimers, which then translocate into the nucleus. 4,21,22,24,66 In the nucleus, pSTAT3 dimers bind to specific DNA response elements in the promoters that activate the transcription of target genes that favor the development, progression, and maintenance of HNSCC and many other tumors.…”

Section: Discussionmentioning

confidence: 99%

“…21,22,24,66 JAK-mediated phosphorylation of the tyrosine-705 residue of STAT3 recruited to the activated IL-6/IL-6Ra/gp130/JAK complex enables reciprocal interactions between SH2 domains of pSTAT3 monomers to form dimers, which then translocate into the nucleus. 4,21,22,24,66 In the nucleus, pSTAT3 dimers bind to specific DNA response elements in the promoters that activate the transcription of target genes that favor the development, progression, and maintenance of HNSCC and many other tumors. [1][2][3][4]7 However, IL-6 can also activate signaling in tissues and cells that do not express the IL-6Ra receptor by a trans-signaling process.…”

Section: Discussionmentioning

confidence: 99%

HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

Johnston

Sen

Hua

et al. 2015

ASSAY and Drug Development Technologies

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Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC 50 assays, and an IFNc-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC 50 s against IFN-c-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ‡70% at 20 lM; their pSTAT3 activation IC 50 s were £25 lM; they were ‡2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ‡90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC 50 s £20 lM and 13 were ‡3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC 50 s £ 20 lM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton.

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“…The program, as its name indicates, docks two compounds simultaneously using a scoring function that evaluates docking of each molecule on the target protein with the AutoDock4 scoring function [85] and interaction between the compounds. MLSD was applied to design a SMPPII for the IL-6/GP130 interface [86]. Before running MLSD, the authors identified hotspot residues by molecular dynamics simulation, and defined a docking box that covers the hotspots.…”

Section: Computational Methods 2: Hot Spots and Fragment-based Metmentioning

confidence: 99%

“…MLSD identified potent fragment combinations, and the combinations were further grown to full ligands, which were found to be similar to two existing drugs (drug repositioning). The identified drugs from repositioning were validated as SMPPIIs by experiment [86]. …”

Section: Computational Methods 2: Hot Spots and Fragment-based Metmentioning

confidence: 99%

In silico structure-based approaches to discover protein-protein interaction-targeting drugs

Shin

Christoffer

Kihara

2017

Methods

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A core concept behind modern drug discovery is finding a small molecule that modulates a function of a target protein. This concept has been successfully applied since the mid-1970s. However, the efficiency of drug discovery is decreasing because the druggable target space in the human proteome is limited. Recently, protein-protein interaction (PPI) has been identified as an emerging target space for drug discovery. PPI plays a pivotal role in biological pathways including diseases. Current human interactome research suggests that the number of PPIs ranges from 130,000 to 650,000, and only a small number of them have been targeted as drug targets. For traditional drug targets, in silico structure-based methods have been successful in many cases. However, their performance suffers on PPI interfaces because PPI interfaces are different in five major aspects: From a geometric standpoint, they have relatively large interface regions, flat geometry, and the interface surface shape tends to fluctuate upon binding. Also, their interactions are dominated by hydrophobic atoms, which is different from traditional binding-pocket-targeted drugs. Finally, PPI targets usually lack natural molecules that bind to the target PPI interface. Here, we first summarize characteristics of PPI interfaces and their known binders. Then, we will review existing in silico structure-based approaches for discovering small molecules that bind to PPI interfaces.

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Drug Design Targeting Protein–Protein Interactions (PPIs) Using Multiple Ligand Simultaneous Docking (MLSD) and Drug Repositioning: Discovery of Raloxifene and Bazedoxifene as Novel Inhibitors of IL-6/GP130 Interface

Cited by 131 publications

References 35 publications

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

Role of the Axonal Initial Segment in Psychiatric Disorders: Function, Dysfunction, and Intervention

HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

In silico structure-based approaches to discover protein-protein interaction-targeting drugs

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