Pharmacophore mapping based inhibitor selection and molecular interaction studies for identification of potential drugs on calcium activated potassium channel blockers, tamulotoxin

Abstract

Background: Tamulotoxin (TmTx) from Buthus tamulus was found to be a highly venomous toxin which accelerates the neurotransmitter release that directly affects the cardiovascular tissues and the respiratory system leading to death. TmTx from red Indian scorpion is a crucial inhibitor for Ca2+ activated K+ channel in humans. Objective: The study is aimed at the identification of potential inhibitors of TmTx through pharmacophore based inhibitor screening and understanding the molecular level interactions. Materials and Method: The potential inhibitors for TmTx were identified using pharmacophore model based descriptor information present in existing drugs with the analysis of pharmacokinetic properties. The compounds with good ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) descriptors were subjected to molecular interaction studies. The stability of bound toxin-inhibitor complex was studied using molecular dynamics simulation over a period of one nanosecond. Results: From a dataset of 3406 compounds, few compounds were selected as potential inhibitors based on the generated best pharmacophore models, pharmacokinetic analysis, molecular docking and molecular dynamics studies. Conclusion: In conclusion, two compounds containing better inhibition properties against TmTx are suggested to be better lead molecules for drug development in future and this study will help us to explore more inhibitors from natural origin against tamulotoxin.