BetaSCPWeb: side-chain prediction for protein structures using Voronoi diagrams and geometry prioritization

Ryu, Joonghyun; Lee, Mokwon; Cha, Jehyun; Laskowski, Roman A.; Ryu, Seong Eon; Kim, Deok Soo

doi:10.1093/nar/gkw368

Cited by 35 publications

(19 citation statements)

References 29 publications

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“…First, cocrystallized conformation of L 90–97 , L 89–98 , and L 88–99 was stripped from their complex crystal structure with TβRII, and then, their two ends residues were virtually mutated to cysteine as two “anchors” to create a disulfide bond bridging them. The virtual mutagenesis was performed with the Voronoi diagram‐based BetaSCPWeb approach, and then, a disulfide bond was manually modeled between the mutant cysteine residues to cyclize the three peptides. Next, the resulting cyclic peptides were separately subjected to 50‐ns MD simulations to relax the artificial system.…”

Section: Resultsmentioning

confidence: 99%

Structure‐based derivation of peptide inhibitors to target TGF‐β1 receptor for the suppression of hypertrophic scarring fibroblast activation

Yang

Zheng

et al. 2017

Chem Biol Drug Des

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The intermolecular recognition and interaction between human transforming growth factor β-1 (TGF-β1) and its cognate receptor TβRII have been implicated in the pathological condition of hypertrophic scarring (HS). Here, we attempted to rationally derive peptide inhibitors from the complex interface of TGF-β1 with TβRII to disrupt such interaction for the suppression of fibroblast activation involved in HS. A synthetic strategy that integrated computational design and fluorescence-based assay was described to examine the structural basis and energetic property of TGF-β1-TβRII crystal structure, from which a small peptide segment in the complex binding site was stripped artificially. Molecular dynamics simulations revealed that the linear peptide possesses a large intrinsic disorder that would incur considerable entropy penalty upon binding to TβRII; the peptide segment was then extended and cyclized by introducing a disulfide bond across its terminal residues that were premutated to cysteine. Normal mode analysis indicated that, as expected, the peptide flexibility was largely reduced upon the cyclization, and thus, the entropy penalty was minimized substantially, consequently promoting the spontaneous binding of peptide to TβRII. Fluorescence polarization assay confirmed that all linear peptides are typical non-binders of TβRII (K = ND), while the designed cyclic peptides exhibit moderate or high affinity with K at micromolar level.

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Section: Resultsmentioning

confidence: 99%

Structure‐based derivation of peptide inhibitors to target TGF‐β1 receptor for the suppression of hypertrophic scarring fibroblast activation

Yang

Zheng

et al. 2017

Chem Biol Drug Des

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“…The crystal complex structures of EGFR T790M/V948R kinase domain with four allosteric inhibitors EAI001, EAI045, JBJ-04-125-02 and DDC4002 have been solved by X-ray crystallography and were retrieved from the protein data bank (PDB) database [27] : 5D41, 6P1L, 6DUK and 6P1D, respectively. Here, the two mutant residues Met790 and Arg948 in the complex kinase domain can be computationally mutated inversely to their wild-type counterpart residues Thr790 and Val948 using the BetaSCPWeb method, [28] during which the effect of protein context on the mutated residues was considered. [29,30] Molecular docking calculations were performed with the AutoDock Vina program [31] to predict the binding modes of the other five allosteric inhibitors (JBJ-02-112-05, JBJ-07-149, F I G U R E 7 Chemical structures of 9 EGFR allosteric inhibitors.…”

Section: Complex Modelingmentioning

confidence: 99%

Noncognate HER2 sensitivity to cognate EGFR allosteric inhibitors at molecular level: New uses for old drugs in gynecological tumors

Hao

Liu

et al. 2021

J Chinese Chemical Soc

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Human epidermal growth factor receptor (EGFR) of the ErbB family kinases is a well-established therapeutic target for malignant lung cancer, which, however, has been observed to cause the dramatic drug resistance to almost all first-to third-generation ATP-competitive inhibitors with the T790M/C797S doublemutation at the peripheral region of its kinase active site. In recent years, allosteric inhibition of the EGFR kinase domain has evolved rapidly to overcome these clinically significant drug-resistant mutations, leading to the discovery of a number of EGFR allosteric inhibitors. In the present study, we attempted to systematically evaluate the molecular sensitivity of existing cognate EGFR allosteric inhibitors to their noncognate HER2 target -another druggable ErbB member that is a potential therapeutic target of diverse gynecological tumors such as breast, cervical and ovarian cancers, and shares high conservation with EGFR but still has no cognate allosteric inhibitors specifically developed for it. An integrative strategy that combined molecular modeling and biochemical inhibition assay was described to investigate the structural basis, energetics property, and dynamics behavior involved in the intermolecular interaction between the HER2 kinase domain and nine reported EGFR allosteric inhibitors at a molecular level. The inhibitor response to HER2 T798M/C805S doublemutation was also examined and compared with their response to counterpart EGFR T790M/C797S double-mutation. It is revealed that the EGFR allosteric inhibitors can also effectively target HER2 kinase with a similar or moderately decreased potency; they exhibit a consistent response profile to EGFR and HER2 counterpart mutations. In addition, the HER2 T798M mutation was found to considerably sensitize allosteric inhibitors EAI045 and JBJ-04-125-02 by creating additional noncovalent interactions between them, while the HER2 C805S mutation was observed to have no essential effect on most allosteric inhibitors due to its spatial separation from the kinase allosteric site.

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“…Instead, virtual residue mutagenesis (VRM) and statistical modeling (Zhou et al 2013ab) were carried out to computationally mutate homologous protein templates to the three-dimensional structures of mouse kinases (except p38α as well as Erk2 and Jnk1). Here, the VRM was performed using BetaSCPWeb server (Ryu et al 2016).…”

Section: Conventional Mouse Mapk Kinasesmentioning

confidence: 99%

Integrative identification of unexpected kinase–inhibitor interactions in the MAPK-mediated proliferation and differentiation of Mc3T3-E1 osteoblasts

Zhao¹,

Huang²,

Tian³

et al. 2019

gpb

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Kinase-targeted therapy is a new and promising approach to disease treatment. However, some kinase inhibitors have been observed to cause an off-target adverse risk for skeletal system by influencing the growth of osteoblasts. It is known that the proliferation and differentiation of osteoblasts are essentially regulated by MAPK signaling pathway, and many off-target events are considered to influence this pathway. Here, the unexpected MAPK-inhibitor interactions in mouse MC3T3-E1 osteoblastic cells were investigated in detail using an integrative protocol. With bioinformatics analysis we successfully profiled a systematic noncognate interaction spectrum for off-target kinase inhibitors against mouse MAPK kinases, from which 13 potential MAPK-inhibitor interactions were identified. The inhibitors Nilotinib, Dasatinib and Bosutinib were suggested as promising candidates; their cytotoxicity on MC3T3-E1 and inhibitory activity against MAPK kinase were tested at cellular and molecular levels, respectively. We also tested two known MAPK inhibitors SP600125 and SB203580 as positive controls. Consequently, the Dasatinib was found to have high off-target risk for unexpectedly targeting osteoblast MAPK signaling pathway.

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BetaSCPWeb: side-chain prediction for protein structures using Voronoi diagrams and geometry prioritization

Cited by 35 publications

References 29 publications

Structure‐based derivation of peptide inhibitors to target TGF‐β1 receptor for the suppression of hypertrophic scarring fibroblast activation

Structure‐based derivation of peptide inhibitors to target TGF‐β1 receptor for the suppression of hypertrophic scarring fibroblast activation

Noncognate HER2 sensitivity to cognate EGFR allosteric inhibitors at molecular level: New uses for old drugs in gynecological tumors

Integrative identification of unexpected kinase–inhibitor interactions in the MAPK-mediated proliferation and differentiation of Mc3T3-E1 osteoblasts

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