Exploration of SAM-I riboswitch inhibitors: In-Silico discovery of ligands to a new target employing multistage CADD approaches

Targeting riboswitches, regulatory elements responsible for the expression of essential genes, is taking central stage in the new era of antibacterial medications discovery due to the emergence of antibiotic resistance. The S-Adenosyl methionine-I (SAM-I) riboswitch works through transcription termination in a negative feedback manner modulated by the natural ligand SAM. SAM-I riboswitch is specific to bacteria and found mainly in gram-positive bacteria such as Bacillus anthracis. Analyzing the interactions of the co-crystallized structure of SAM-I riboswitch aptamer with its native ligand SAM clarified the needed chemical structural features to achieve binding. Acknowledging those features, structure-based and ligand-based pharmacophore models were built for filtration use in screening the OTAVA Chemical library and the Pubchem database. For further filtration enhancement, the physicochemical properties of SAM were used as a second filtration criterion. Compounds obtained as output from previous steps were energy minimized, and the lowest energy conformer structures were docked to SAM-I using MOE, v.2019.01. S-score and ligand interactions were used to assess the best hits. This yielded eight promising compounds to which molecular dynamics (MD) simulations with SAM-I aptamer were applied using GROMACS 2020.3 package affirming stable binding interactions and binding energetics similar to SAM. Moreover, pharmacokinetic and drug-like properties of those eight hits were assessed using SWISS-ADME. According to the combined computational methods and PK/Tox assessment, compound 20 was the most promising and thus can be considered a lead for future evaluation and optimization as a candidate new antibacterial agent targeting a new biomolecule eliciting a new mechanism of action.