AlloFinder: a strategy for allosteric modulator discovery and allosterome analyses

Huang, Min; Song, Kun; Liu, Xinyi; Lu, Shaoyong; Shen, Qiancheng; Wang, Renxiao; Gao, Jingze; Hong, Yuanyuan; Li, Qian; Ni, Duan; Xu, Jianrong; Chen, Guoqiang; Zhang, Jian

doi:10.1093/nar/gky374

Cited by 78 publications

(76 citation statements)

References 60 publications

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“…After SAR 650984 had been identified as an allosteric inhibitor of CD38, it was natural to assume that their binding interface (PDB ID: 4CMH; Figure A) was a potential allosteric site. To explore the potential allosteric site of CD38, an online server—AlloFinder, which uses elegant algorithms such as pocket‐based analysis and support vector machine (SVM) classifier to predict the locations of allosteric sites in proteins—was employed. Two sites, shown as Ι and ΙΙ ( Figure B), were highlighted.…”

Section: Resultsmentioning

confidence: 99%

“…Allosteric site prediction and hotspot mapping : The potential allosteric site in the C‐terminal structure of huCD38 containing the substrate‐binding and SAR antibody‐binding domains (PDB ID: 4CMH) was identified by use of the online server AlloFinder . The pseudo‐ligands (in magenta in Figure B) in the predicted sites were generated automatically.…”

Section: Methodsmentioning

confidence: 99%

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Rational Design and Identification of Small‐Molecule Allosteric Inhibitors of CD38

Yang

et al. 2019

ChemBioChem

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CD38 is a multi‐functional signaling enzyme that catalyzes the biosynthesis of two calcium‐mobilizing second messengers: cyclic ADP‐ribose and nicotinic acid adenine dinucleotide phosphate. It also regulates intracellular nicotinamide adenine dinucleotide (NAD) contents, associated with multiple pathophysiological processes such as aging and cancer. As such, enzymatic inhibitors of CD38 offer great potential in drug development. Here, through virtual screening and enzymatic assays, we discovered compound LX‐102, which targets CD38 on the side opposite its enzymatic pocket with a binding affinity of 7.7 μm. It inhibits the NADase activity of CD38 with an IC50 of 14.9 μm. Surface plasmon resonance (SPR) and hydrogen/deuterium exchange and mass spectrometry experiments verified that LX‐102 competitively binds to the epitope of the therapeutic SAR 650984 antibody in an allosteric manner. Molecular dynamics simulation was performed to demonstrate the binding dynamics of CD38 with the allosteric ligand. In summary, we established that the cavity to which SAR 650984 binds was an allosteric site and was accessible for the rational design of small chemical modulators of CD38. The lead compound LX‐102 that we identified in this study could also be a useful tool for probing CD38 functions and promoting drug discovery.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Rational Design and Identification of Small‐Molecule Allosteric Inhibitors of CD38

Yang

et al. 2019

ChemBioChem

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“…Previous studies indicate that the CCD of STAT3 is essential for auto-phosphorylation (Ma et al, 2003; Zhang et al, 2000), and certain proteins could inhibit STAT3 activation by binding to STAT3 CCD domain (Chang et al, 2018; Mattagajasingh et al, 2012). Even K116, a STAT3 allosteric inhibitor, inhibited STAT3 phosphorylation at Tyr705 by binding to the CCD of STAT3 (Huang et al, 2018a). Using molecular docking, we showed that the ASRPS binding region in the CCD domain overlaps with K116 binding (Fig.…”

Section: Discussionmentioning

confidence: 99%

LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis

Wang

Zhu

et al. 2019

Journal of Experimental Medicine

163

101

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Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with the most aggressive phenotype and poor overall survival. Using bioinformatics tools, we identified LINC00908 encoding a 60–aa polypeptide and differentially expressed in TNBC tissues. We named this endogenously expressed polypeptide ASRPS (a small regulatory peptide of STAT3). ASRPS expression was down-regulated in TNBCs and associated with poor overall survival. We showed that LINC00908 was directly regulated by ERα, which was responsible for the differential down-regulation of LINC00908 in TNBCs. ASRPS directly bound to STAT3 through the coiled coil domain (CCD) and down-regulated STAT3 phosphorylation, which led to reduced expression of VEGF. In human endothelial cells, a mouse xenograft breast cancer model, and a mouse spontaneous BC model, ASRPS expression reduced angiogenesis. In a mouse xenograft breast cancer model, down-regulation of ASRPS promoted tumor growth, and ASRPS acted as an antitumor peptide. We presented strong evidence that LINC00908-encoded polypeptide ASRPS represented a TNBC-specific target for treatment.

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“…Various theoretical models have been put forward for computational allosteric site prediction tools, such as the structure‐based model in AlloSite, the Normal mode analysis‐based model in PARS and the topology‐based model in STRESS . In addition, very recent advances such as AlloSigMA, which provides a quantitative tool for analyzing the energetics underlying allosteric communication, and AlloFinder, which supplies allosterome analysis and virtual screening and scoring, may also be useful tools for allosteric target identification within PPI systems. As a result, computational prediction of allosteric sites can be exploited as a starting point for the discovery of allosteric PPI modulators.…”

Section: Discussionmentioning

confidence: 99%

Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Zhang

2019

Medicinal Research Reviews

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Protein‐protein interactions (PPIs) are closely implicated in various types of cellular activities and are thus pivotal to health and disease states. Given their fundamental roles in a wide range of biological processes, the modulation of PPIs has enormous potential in drug discovery. However, owing to the general properties of large, flat, and featureless interfaces of PPIs, previous attempts have demonstrated that the generation of therapeutic agents targeting PPI interfaces is challenging, rendering them almost “undruggable” for decades. To date, rapid progress in chemical and structural biology techniques has promoted the exploitation of allostery as a novel approach in drug discovery. By attaching to allosteric sites that are topologically and spatially distinct from PPI interfaces, allosteric modulators can achieve improved physiochemical properties. Thus, allosteric modulators may represent an alternative strategy to target intractable PPIs and have attracted intense pharmaceutical interest. In this review, we first briefly introduce the characteristics of PPIs and then present different approaches for investigating PPIs, as well as the latest methods for modulating PPIs. Importantly, we comprehensively review the recent progress in the development of allosteric modulators to inhibit or stabilize PPIs. Finally, we conclude with future perspectives on the discovery of allosteric PPI modulators, especially the application of computational methods to aid in allosteric PPI drug discovery.

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AlloFinder: a strategy for allosteric modulator discovery and allosterome analyses

Cited by 78 publications

References 60 publications

Rational Design and Identification of Small‐Molecule Allosteric Inhibitors of CD38

Rational Design and Identification of Small‐Molecule Allosteric Inhibitors of CD38

LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis

Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

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