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Biology and Distribution of Venomous Snakes of Medical Importance and The Composition of Snake Venoms
Published in Jürg Meier, Julian White, Handbook of: Clinical Toxicology of Animal Venoms and Poisons, 2017
Three groups of snake neurotoxins acting at the presynaptic level have to be distinguished: the PLA2-toxins, the dendrotoxins and the fasciculins (see Figure 7). All PLA2-toxins found in elapid and some viperid snake venoms have a basic phospholipase A2 in common that may be complexed with acidic, basic or neutral protein units. PLA2-Toxins may consist of a single chain (e.g. Caudoxin from Bitis caudalis venom, Notexin from Notechis scutatus venom, Ammodytoxin from Vipera ammodytes venom), of two chains (β-Bungarotoxin from Bungarus multicinctus venom), they may form a two protein complex (e.g. Crotoxin from Crotalus durissus terrificus venom, Mojave toxin from Crotalus scutulatus venom) or they may consist of a multiple protein complex (e.g. Taipoxin from Oxyuranus scutellatus venom, Textilotoxin from Pseudonaja textilis venom). They all act in a complex, usually triphasic manner55,56,70. Probably due to their binding at the presynaptic nerve membrane, a short inhibition of neurotransmitter release is observed. In a second phase there is an increasing neurotransmitter release due to the action of the phospholipase, finally followed by a block, when all neurotransmitter is released74. For crotoxin, a two component neurotoxin, it has been shown that the non-enzymatic component A increases the pharmacological efficacy of the PLA2-component B, since component A directs component B onto its acceptor at the neuromuscular junctions. In so doing component A prevents the PLA2-component B from being bound onto inefficient binding sites249. For detailed reviews on PLA2-toxins, see 82,85. Dendrotoxins are very basic single chain polypeptides consisting of 57 to 60 amino acid residues, cross-linked by three disulphide bridges. They are devoid of enzymatic activity and block certain potassium channels in nerve membranes, thus facilitating the release of neurotransmitters (for a review, see86). Dendrotoxins have only been found in venoms of the African mambas (Dendroaspis species). Dendrotoxins share structural homology with the bovine pancreatic trypsin inhibitor (aprotinin, BPTI), although they neither inhibit trypsin nor other trypsin-like serine proteinases. Fasciculins are again neurotoxins, which are only found in Mamba venoms (Dendroaspis species). They belong to a toxin group, which was named “angusticeps-type" toxins (from Dendroaspis angusticeps, the Common Mamba). These toxins share structural homology with postsynaptic neurotoxins and snake cardiotoxins, although they are immunologically distinct from all other snake toxins. Fasciculins are potent inhibitors of cholineesterases from different sources. Therefore, they potentiate the action of acetylcholine and cause a generalized muscle fasciculation in vivo (for a review, see87).
Synthesis and biological assessment of KojoTacrines as new agents for Alzheimer’s disease therapy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Youssef Dgachi, Hélène Martin, Rim Malek, Daniel Jun, Jana Janockova, Vendula Sepsova, Ondrej Soukup, Isabel Iriepa, Ignacio Moraleda, Emna Maalej, M. Carmo Carreiras, Bernard Refouvelet, Fakher Chabchoub, José Marco-Contelles, Lhassane Ismaili
For docking experiments, Autodock Vina32 software was employed. Compounds (R)-KT2d and (S)-KT2d were prepared with Discovery Studio, version 2.1, software package, using standard bond lengths and bond angles. With the CHARMm force field33 and partial atomic charges, the molecular geometries of the compounds were energy-minimized using the adopted-based Newton–Rapson algorithm until the rms gradient was below 0.01 kcal (mol-Å)−1. Three-dimensional crystal structure of hAChE complexed with fasciculin-II (PDB: 1B41) was retrieved from the Protein Data Bank (PDB). Before docking the ligands into the protein, this was prepared by removing all water molecules, heteroatoms, any co-crystallized solvent, and the ligand. Protein model tool in Discovery Studio, version 2.1, software package was used to assign proper bonds, bond orders, hybridization, and charges. CHARMm force field was applied using the receptor-ligand interactions tool in Discovery Studio, version 2.1, software package. AutoDockTools (ADT; version 1.5.4) was used to add hydrogens and partial charges for proteins and ligands using Gasteiger charges. Selected side chains into the target macromolecule are allowed to change their conformations at the same time as the ligand that is being docked. Using the AutoTors module, the macromolecule side chains chosen to be flexible are Trp286, Tyr124, Tyr337, Tyr72, Asp74, Thr75, Trp86 and Tyr341. The docking box was displayed using ADT and it is big enough to include whole protein target (“blind docking”). A grid box of 60 × 60 × 72 with grid point spacing of 1 Ǻ was positioned at the middle of the protein (x = 116.546; y = 110.33; z = −134.181). Default parameters were used except num_modes, which was set to 40. The AutoDock Vina docking procedure used was previously validated25. The scoring function of AutoDock Vina was chosen, and the docking poses for each ligand were analyzed by examining their relative total energy score. The more energetically favorable conformation was selected as the best pose. The structures of the macromolecule and ligands, as well as the docking results, were processed using Discovery Studio software.