Thiamin pyrophosphate riboswitch is going to accept new compounds as antibacterial to repress gene expression

Thiamine pyrophosphate (TPP) riboswitch controls gene expression through binding of small molecules to the aptamer sequence. As this sequence is found in bacteria, it can be one target of antibacterial. A QSAR study in our laboratory using experimentally tested compounds indicated that among 1875 descriptors, four of them (Alogp2 with lipophilic (hydrophobicity) property, ionization energy attributed to AATSC6i; charge indicated by ATSC0c and βLUMO indicative of sensitivity of a molecule to be attacked by nucleophiles) are the most important properties which altogether consist the driving force of ligand binding to the binding site. Approximately 10000 compounds were generated followed by applying the QSAR model, docking and ADME (absorption, distribution, metabolism, and excretion) criteria to predict the activity and quality of the compounds respectively. pKd prediction of the compounds using QSAR indicated that the activity of the some of the designed ligands are between 8.00 to 9.00, therefore these were selected to predict ΔG by docking the molecules in AutoDock Vina which offered some ligands with ΔG between -9.7 to -11.0. kcal/mol. The quality of ligands from ADME standing point was verified using SWISSADME. ADME quality study indicated that these compounds are not P-gp substrate, molecular weight is less than 500 Da and the selected compounds passed Lipinski rule of five. The best compounds are under synthesis in our Lab.

Keywords:

QSAR , TPP Riboswitch , ligand design