NMR-Based Structural Characterization of a Two-Disulfide-Bonded Analogue of the FXIIIa Inhibitor Tridegin: New Insights into Structure–Activity Relationships

The saliva of blood-sucking leeches contains a plethora of anticoagulant substances. One of these compounds derived from Haementeria ghilianii, the 66mer three-disulfide-bonded peptide tridegin, specifically inhibits the blood coagulation factor FXIIIa. Tridegin represents a potential tool for antithrombotic and thrombolytic therapy. We recently synthesized two-disulfide-bonded tridegin variants, which retained their inhibitory potential. For further lead optimization, however, structure information is required. We thus analyzed the structure of a two-disulfide-bonded tridegin isomer by solution 2D NMR spectroscopy in a combinatory approach with subsequent MD simulations. The isomer was studied using two fragments, i.e., the disulfide-bonded N-terminal (Lys1–Cys37) and the flexible C-terminal part (Arg38–Glu66), which allowed for a simplified, label-free NMR-structure elucidation of the 66mer peptide. The structural information was subsequently used in molecular modeling and docking studies to provide insights into the structure–activity relationships. The present study will prospectively support the development of anticoagulant-therapy-relevant compounds targeting FXIIIa.

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Identification and Initial Structure−Activity Relationships of a Novel Class of Nonpeptide Inhibitors of Blood Coagulation Factor Xa

Journal of Medicinal Chemistry ◽

10.1021/jm970482y ◽

1998 ◽

Vol 41 (4) ◽

pp. 437-450 ◽

Cited By ~ 24

Author(s):

Scott I. Klein ◽

Mark Czekaj ◽

Charles J. Gardner ◽

Kevin R. Guertin ◽

Daniel L. Cheney ◽

...

Keyword(s):

Blood Coagulation ◽

Factor Xa ◽

Coagulation Factor ◽

Initial Structure ◽

Structure Activity Relationships ◽

Structure Activity

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Antiplasmodial Bis-Indole Alkaloids from the Bark of Flindersia pimenteliana

Planta Medica ◽

10.1055/a-1028-7786 ◽

2019 ◽

Vol 86 (01) ◽

pp. 19-25 ◽

Cited By ~ 2

Author(s):

Luke P. Robertson ◽

Leonardo Lucantoni ◽

Vicky M. Avery ◽

Anthony R. Carroll

Keyword(s):

Plasmodium Falciparum ◽

Spectroscopic Data ◽

Indole Alkaloids ◽

2D Nmr ◽

Antiplasmodial Activity ◽

Structure Activity Relationships ◽

Structure Activity ◽

Ic50 Values ◽

Significant Attention

AbstractThree new (1–3) and 2 known (4–5) bis-indole alkaloids were identified from the bark of Flindersia pimenteliana (Rutaceae). The structures of 1–3 were elucidated on the basis of their (+)-HRESESIMS and 2D NMR spectroscopic data. Antiplasmodial activity for 1–3 against chloroquine sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum is also reported, with IC50 values ranging from 0.96 to 2.41 µg/mL. These results expand our knowledge of the structure-activity relationships of potently antiplasmodial isoborreverine-type alkaloids, the bioactivity of which have recently attracted significant attention in the literature.

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Design and Structure−Activity Relationships of Potent and Selective Inhibitors of Blood Coagulation Factor Xa

Journal of Medicinal Chemistry ◽

10.1021/jm990040h ◽

1999 ◽

Vol 42 (18) ◽

pp. 3557-3571 ◽

Cited By ~ 28

Author(s):

William R. Ewing ◽

Michael R. Becker ◽

Vincent E. Manetta ◽

Roderick S. Davis ◽

Henry W. Pauls ◽

...

Keyword(s):

Blood Coagulation ◽

Factor Xa ◽

Coagulation Factor ◽

Selective Inhibitors ◽

Structure Activity Relationships ◽

Structure Activity

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Statistical analysis and shape recognition: Applications to MD simulations, conformational analysis and structure-activity relationships

Trends in QSAR and Molecular Modelling 92 ◽

10.1007/978-94-011-1472-1_33 ◽

1993 ◽

pp. 216-219 ◽

Cited By ~ 3

Author(s):

Gérard Grassy ◽

Roger Lahana

Keyword(s):

Statistical Analysis ◽

Conformational Analysis ◽

Shape Recognition ◽

Md Simulations ◽

Structure Activity Relationships ◽

Structure Activity

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New Terpendole Congeners, Inhibitors of Sterol O-Acyltransferase, Produced by Volutella citrinella BF-0440

Molecules ◽

10.3390/molecules25133079 ◽

2020 ◽

Vol 25 (13) ◽

pp. 3079

Author(s):

Elyza Aiman Azizah Nur ◽

Keisuke Kobayashi ◽

Ai Amagai ◽

Taichi Ohshiro ◽

Hiroshi Tomoda

Keyword(s):

Inhibitory Activity ◽

2D Nmr ◽

Culture Broth ◽

Ring System ◽

Indole Ring ◽

Ring Systems ◽

Structure Activity Relationships ◽

Structure Activity ◽

Activity Structure

New terpendoles N-P (1–3) were isolated along with 8 structurally related known compounds including terpendoles and voluhemins from a culture broth of the fungus Volutella citrinella BF-0440. The structures of 1–3 were elucidated using various spectroscopic experiments including 1D- and 2D-NMR. All compounds 1–3 contained a common indole–diterpene backbone. Compounds 2 and 3 had 7 and 6 consecutive ring systems with an indole ring, respectively, whereas 1 had a unique indolinone plus 4 consecutive ring system. Compounds 2 and 3 inhibited both sterol O-acyltransferase 1 and 2 isozymes, but 1 lost the inhibitory activity. Structure–activity relationships of fungal indole–diterpene compounds are discussed.

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3D-QSAR, Molecular Docking, and MD Simulations of Anthraquinone Derivatives as PGAM1 Inhibitors

Frontiers in Pharmacology ◽

10.3389/fphar.2021.764351 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuwei Wang ◽

Yifan Guo ◽

Shaojia Qiang ◽

Ruyi Jin ◽

Zhi Li ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Rational Design ◽

Binding Free Energy ◽

3D Qsar ◽

Md Simulations ◽

Structure Activity Relationships ◽

Structure Activity ◽

Wide Range ◽

Anthraquinone Derivatives

PGAM1 is overexpressed in a wide range of cancers, thereby promoting cancer cell proliferation and tumor growth, so it is gradually becoming an attractive target. Recently, a series of inhibitors with various structures targeting PGAM1 have been reported, particularly anthraquinone derivatives. In present study, the structure–activity relationships and binding mode of a series of anthraquinone derivatives were probed using three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, r2 = 0.97, q2 = 0.81) and comparative molecular similarity indices analysis (CoMSIA, r2 = 0.96, q2 = 0.82) techniques were performed to produce 3D-QSAR models, which demonstrated satisfactory results, especially for the good predictive abilities. In addition, molecular dynamics (MD) simulations technology was employed to understand the key residues and the dominated interaction between PGAM1 and inhibitors. The decomposition of binding free energy indicated that the residues of F22, K100, V112, W115, and R116 play a vital role during the ligand binding process. The hydrogen bond analysis showed that R90, W115, and R116 form stable hydrogen bonds with PGAM1 inhibitors. Based on the above results, 7 anthraquinone compounds were designed and exhibited the expected predictive activity. The study explored the structure–activity relationships of anthraquinone compounds through 3D-QSAR and molecular dynamics simulations and provided theoretical guidance for the rational design of new anthraquinone derivatives as PGAM1 inhibitors.

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