IDENTIFICATION OF POTENTIAL BIOACTIVE DSBA-INHIBITORS AS AN ANTIMICROBIAL RESTORATION STRATEGY: AN IN-SILICO SCREENING AND ADMET STUDY

Antimicrobial resistance continues to cause antibiotics treatment failure and millions of deaths globally. Inhibition of a double-stranded binding protein-A enzyme (DsbA), machinery in bacteria resistance and pathogenesis mechanisms make the bacteria vulnerable to existing antibiotics, allowing restoration of antimicrobial efficacy. However, there is a gap in identifying bioactive and safe DsbA-inhibitors as a therapeutic restoration strategy. In this in-silico screening study, a co-crystallized E. coli-DsbA enzyme protein was used as the target. Seven bioactive ligands: linoleic acid, aloesin, azadirachtin, nimbin, palmitic acid, stearic acid, and aloeresin-A, showed maximum docking scores of low binding affinity (kcal/mol): -6.8345, – 5.9434, – 7.2810, -6.2394, -6.5958, -6.7170 and -6.9554 respectively, lower than the standard (9AG): -4. 6919. The ligands obeyed Lipinski’s rule of 5. The Root Mean Square Deviation (RMSD) of E. coli-DsbA complexes with azadirachtin, and aloeresin-A displayed remarkable stability throughout the simulations. Molecular dynamics simulation on azadirachtin and aloeresin-A showed great docking scores and modes over 10000ps and revealed lowest binding affinity scores, remain stable in the active site. Additionally, astructural-activity relationship study was done on azadirachtin as the top-ranking ligand in which 2-oxopropanal moiety revealed lowest binding energy of -7.4190(kcal/mol). Finally, the test ligands were subjected to in-silico ADMET prediction analysis and showed good pharmacokinetics drug likeness properties and safety. The results obtained are a great step in discovering safe DsbA-inhibitors (antivirulence agent) for in-vitro and in-vivo validation studies in the antibiotics restoration strategy against resistant bacteria.