In-silico-based toxicity investigation of natural repellent molecules against the human proteome: A safety profile design v1
Anagha Shamsundar Setlur, Chandrashekar K, Vartul Panhalkar, Sonia Sharma, Manas Sarkar, Vidya Niranjan · 2023
Comprehending the toxicity and other adverse effects of any given set of potential natural repellent molecules against various proteins in humans is essential to determine their safety prior to their use in formulations. An in-silico computational protocol provided in this article can be used to determine the toxicity of any given molecule against the entire human proteome and thus build a safety profile for the same. Preliminary toxicity predictions for oral, dermal and inhalation routes were made for the natural small molecules using computational tools such as Protox-II, SwissADME and T.E.S.T. The screening of the whole proteome to determine the off-targets was then conducted for a given set of natural small molecules with similar mode of action. Tools such as LigTMap, PharmMapper, Swiss Target Predictions and SuperPRED were used for off-target determination. Selection criteria were employed to shortlist the most interacting and probable off-targets to the ligands. These shortlisted protein targets were then manually docked using Schrodinger and the best and poor docked complexes were simulated at 100ns in the Desmond suite of Schrodinger to assess the stability of binding. The final safety profile was then designed after collating all the results obtained from the above-mentioned analyses, considering all parameters. The recommended set of natural small molecules can be visualized for better understandability using a bar chart from the safety profile created for the given set of molecules. This protocol can thus be employed for testing the toxicity and safety of any ligand computationally, so these predictions maybe used prior to any in-vitro studies, to understand the preliminary safety challenges. Keywords: Human safety evaluation, proteome, natural small molecules, repellents, off-targets and toxicity, molecular docking and simulations