title: Potential Implications for Designing Drugs Against the Brown Spider Venom Phospholipase-D.
abstract: Loxoscelism refers to the clinical symptoms that develop after brown spider bites. Brown spider venoms contain several phospholipase-D isoforms, which are the main toxins responsible for both the cutaneous and systemic effects of loxoscelism. Understanding of the phospholipase-D catalytic mechanism is crucial for the development of specific treatment that could reverse the toxic effects caused by the spider bite. Based on enzymatic, biological, structural, and thermodynamic tests, we show some features suitable for designing drugs against loxoscelism. Firstly, through molecular docking and molecular dynamics predictions, we found three different molecules (Suramin, Vu0155056, and Vu0359595) that were able to bind the enzyme's catalytic site and interact with catalytically important residues (His12 or His47) and with the Mg2+co-factor. The binding promoted a decrease in the recombinant brown spider venom phospholipase-D (LiRecDT1) enzymatic activity. Furthermore, the presence of the inhibitors reduced the hemolytic, dermonecrotic, and inflammatory activities of the venom toxin in biological assays. Altogether, these results indicate the mode of action of three different LiRecDT1 inhibitors, which were able to prevent the venom toxic effects. This strengthen the idea of the importance of designing a specific drug to treat the serious clinical symptoms caused by the brown spider bite, a public health problem in several parts of the world, and until now without specific treatment. J. Cell. Biochem. 118: 726-738, 2017. © 2016 Wiley Periodicals, Inc.
authors: Department of Cell Biology, Federal University of Paraná (UFPR), Curitiba, PR, Brazil.
authors: Daniele
authors: D
authors: Chaves-Moreira
authors: Multi-user Center of Biomolecular Innovation, Physics Department, Paulista State University (UNESP), São José do Rio Preto, SP, Brazil.
authors: Fábio Rogério
authors: FR
authors: de Moraes
authors: Multi-user Center of Biomolecular Innovation, Physics Department, Paulista State University (UNESP), São José do Rio Preto, SP, Brazil.
authors: Ícaro Putinhon
authors: ÍP
authors: Caruso
authors: Department of Cell Biology, Federal University of Paraná (UFPR), Curitiba, PR, Brazil.
authors: Olga Meiri
authors: OM
authors: Chaim
authors: Department of Cell Biology, Federal University of Paraná (UFPR), Curitiba, PR, Brazil.
authors: Andrea
authors: A
authors: Senff-Ribeiro
authors: Multi-user Center of Biomolecular Innovation, Physics Department, Paulista State University (UNESP), São José do Rio Preto, SP, Brazil.|Department of Biosciences, COMSATS Institute of Information Technology, Park, Road, Islamabad, 45550, Pakistan.
authors: Anwar
authors: A
authors: Ullah
authors: Multi-user Center of Biomolecular Innovation, Physics Department, Paulista State University (UNESP), São José do Rio Preto, SP, Brazil.
authors: Luciane Sussuchi
authors: LS
authors: da Silva
authors: Multi-user Center of Biomolecular Innovation, Physics Department, Paulista State University (UNESP), São José do Rio Preto, SP, Brazil.
authors: Jorge
authors: J
authors: Chahine
authors: Multi-user Center of Biomolecular Innovation, Physics Department, Paulista State University (UNESP), São José do Rio Preto, SP, Brazil.
authors: Raghuvir K
authors: RK
authors: Arni
authors: Department of Cell Biology, Federal University of Paraná (UFPR), Curitiba, PR, Brazil.
authors: Silvio Sanches
authors: SS
authors: Veiga
mesh_terms: D000818:Animals; D060829:Arthropod Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D001562:Benzimidazoles / Q000494:pharmacology; D063287:Brown Recluse Spider / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009336:Necrosis; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000473:pathology; D001098:Spider Bites / Q000188:drug therapy / Q000201:enzymology; D013111:Spider Venoms / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D013498:Suramin / Q000494:pharmacology
chemical_list: D060829:Arthropod Proteins; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D008024:Ligands; C585270:N-(2-(4-(2-oxo-2,3-dihydro-1H-benzo(d)imidazol-1-yl)piperidin-1-yl)ethyl)-2-naphthamide; D010880:Piperidines; D011994:Recombinant Proteins; D013111:Spider Venoms; C516323:dermonecrotic toxin, Loxosceles intermedia; C055161:loxosceles venom; D013498:Suramin; D010727:Phosphoric Diester Hydrolases; D010739:Phospholipase D
keywords: BROWN SPIDER; INHIBITOR; LOXOSCELES INTERMEDIA; RECOMBINANT TOXIN; VENOM PHOSPHOLIPASE-D