Characterization of suramin binding sites on the human group IIA secreted phospholipase A2 by site-directed mutagenesis and molecular dynamics simulation

Aragão, Elisangela Aparecida; Vieira, Davi Serradella; Chioato, Lucimara; Ferreira, Tiago Luiz; Lourenzoni, Marcos Roberto; Silva, Samuel Reghim; Ward, Richard J.

doi:10.1016/j.abb.2012.01.002

Cited by 3 publications

(1 citation statement)

References 30 publications

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“…Such interactions may be the rationale for its toxicity in several cases 39 . Of late, there have been a plethora of instances highlighting the potential of suramin based therapeutics: treating severe fever with thrombocytopenia syndrome caused by bunyavirus (by inhibiting viral nucleocapsid protein) 48 , malaria (by inhibiting falcipain-2, a cysteine protease) 49 , gastroenteritis (by inhibiting RNA dependent RNA polymerase in Noroviruses) 50 , EV71 infection 51 , tuberculosis (by inhibiting RecA) 52 and Dengue virus infection (by inhibiting envelope protein binding to target cell heparan sulfate).…”

Section: Analysis Of Suramin Binding To a Set Of Nine Non-homologous mentioning

confidence: 99%

DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

Chakraborty

2016

F1000Res

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The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already ’plastic’ binding site. Thus, DOCLASP presents a method for ’soft docking’ ligands to proteins with low computational requirements.

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Section: Analysis Of Suramin Binding To a Set Of Nine Non-homologous mentioning

confidence: 99%

DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

Chakraborty

2016

F1000Res

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Structure Elucidation of Helical Aromatic Foldamer–Protein Complexes with Large Contact Surface Areas

Reddy

d’Estaintot

Granier

et al. 2019

Chemistry A European J

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The development of large synthetic ligands could be useful to target the sizeable surface areas involved in protein-protein interactions.H erein,w ep resent long helical aromatic oligoamide foldamersb earing proteinogenic side chainst hat cover up to 450 2 of the human carbonic anhydrase II (HCA) surface. The foldamers are composed of aminoquinolinecarboxylic acids bearing proteinogenic side chains and of more flexible aminomethyl-pyridinecarboxylic acids that enhance helix handedness dynamics. Crystal structures of HCA-foldamer complexes were obtained with a9 -a nd a1 4-mer both showing extensive protein-foldamer hydrophobic contacts. In addition, foldamer-foldamer interactions seem to be prevalent in the crystal packing, leading to the peculiar formation of an HCA superhelix wounda round ar od of stacked foldamers. Solution studies confirmt he positioning of the foldamer at the protein surface as well as ad imerization of the complexes.Aromatic foldamers [1] emerge as an ew class of folded oligomers that may be decorated with proteinogenic side chains to interactw ith proteins [2,3] and nucleic acids, [4,5] ande ventually serve as inhibitors of nucleic acid-protein andp rotein-protein interactions. Amphipathic structures have also been shown to interactw ith, or to insert themselves in,m embranes. [6, 7] Some possess antibiotic activity. [6] Both linear [2,5, 6] and helical [3, 4, 7] foldamers have been developed and varied targets have been identified, including hDM2 and B-cell lymphoma-2 (Bcl-2)r egulator proteins, [2a,d,e] protein precursors of amyloids, [2c, 3a-e] G-quadruplex DNA [4] and some DNA-binding enzymes. [3f] Advantages of aromatic foldamersi nclude their ease of synthesis, for example through solid-phasem ethodologies, [8] and the predictability and stability of their folded conformations in both protica nd aprotics olvents. [9] Becauser elativelyl arge and welldefined folded objects can be produced using aromatic amide backbones, [10] it mayb ee nvisaged to cover large surfacea reas of proteins and nucleic acids. For example, we recently reported protein binding using a9 .2 kDa foldamer mimicking a 16 base-pair DNA duplex. [3f] Nevertheless, designing objects that can recognize large surfacea reas of proteins is difficult: whichs ide chains are to be selecteda nd where should they be located?S ome of the published work concerned mimetics of a-helices, [2] B-DNA, [3f] or natural products. [5] Other approachesuse screening through directed evolution methods. [11] It remains that no general approache xists for the ab initio designo fl arge ligands for ap roteins urface. Structurali nformationa bout aromatic foldamer-protein interactions would constitute af irm stepping-stonef or further design,b ut it can hardlyb eo btained without having reasonable binding affinity in the first place.To overcomet his sort of deadlock, we endeavoredt oi nvestigate foldamer-protein interfaces by confining foldamers at the surface of ap rotein. [12, 13] For example, helical oligoamides based on 8-aminoqu...

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100 Years of Suramin

Wiedemar

Hauser

Mäser

2020

Antimicrob Agents Chemother

145

134

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Suramin is 100 years old and is still being used to treat the first stage of acute human sleeping sickness, caused by Trypanosoma brucei rhodesiense. Suramin is a multifunctional molecule with a wide array of potential applications, from parasitic and viral diseases to cancer, snakebite, and autism. Suramin is also an enigmatic molecule: What are its targets? How does it get into cells in the first place? Here, we provide an overview of the many different candidate targets of suramin and discuss its modes of action and routes of cellular uptake. We reason that, once the polypharmacology of suramin is understood at the molecular level, new, more specific, and less toxic molecules can be identified for the numerous potential applications of suramin.

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Characterization of suramin binding sites on the human group IIA secreted phospholipase A2 by site-directed mutagenesis and molecular dynamics simulation

Cited by 3 publications

References 30 publications

DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

Structure Elucidation of Helical Aromatic Foldamer–Protein Complexes with Large Contact Surface Areas

100 Years of Suramin

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