Computational structure prediction, virtual screening, pharmacokinetic profiling and molecular interaction studies on Na⁺ and Ca²⁺ ion channel blockers of Phoneutria toxins(PhTxs) from Phoneutria nigreventer

Many of the toxins produce a wide range of interaction with many biological macromolecules such as enzymes, ion channels, cellular receptors, etc. Phoneutria nigreventer a poisonous spider produces a cocktail of proteins which affects Na+, Ca2+ and K+ channels. In this work we studied the functional role of the proteins with respect to protein structure which is still unknown. The spider toxin fractions have no experimentally determined three dimensional structures in any of the structural databases. So, comparative modeling method was employed to predict the structure of the toxin fractions and then multiple structure alignment studies were carried out. The fraction that plays a very important role is PhTx26 toxin, which affects the sodium channels and it is the main cause for toxic activity on the cells. More than 300 analogs of derivatives of aspirin as well as derivatives of clove oil were computationally analyzed and further their ADME/Tox profiles were tested. From the ADMET studies we have selected the best analogs that possessed appropriate pharmacokinetic properties and interaction studies were performed for neutralizing the effect of the toxin PhTx26 using the Ligand Fit program of Discovery Studio 2.0. Based on the scoring functions and hydrogen bond interactions we identified the analog of acetylsalicylic acid, “N(4hydroxyphenyl) butanamide” to be the best interacting molecule which may have the efficiency to cure the neurotoxic effect produced by Phoneutria toxins.