Repurposing FDA-approved anti-diabetic drug to target H. pylori peptidyl deformylase using computer-based drug discovery approach

Abstract

ABSTRACT Peptide deformylase (PDF), a metalloenzyme is an important and attractive target in antibacterial drug discovery. It removes the N-formyl group from the nascent peptide and generates a mature N-terminal end of the protein molecule. Acarbose is an FDA-approved microbial origin anti-diabetic drug and is known to alter the gut microbiota in clinical studies. The present study first time identifies the binding efficacy of acarbose isolated from a natural source against PDF. We performed molecular docking and molecular dynamics (MD) simulation studies to check the binding efficacy of acarbose with the catalytic site of Helicobacter pylori PDF. Molecular docking results of acarbose complexed with PDF showed a good docking score (−12.55 kcal/mole) in comparison to standard drug bind with PDF (−8.99 kcal/mole). Interaction with the amino acids (Gly95, Glu139, His138, Gly46 and Glu940) and metal ion present at the catalytic site of the test protein was found to be common in PDF during interaction with the acarbose and actinonin. Various parameters such as RMSD, RMSF, Rg, SASA, Hydrogen-bond formation, energy landscape and principal component analysis showed that the acarbose form stable and energetically stable complex with PDF in comparison to actinonin. Taken together, our study concludes that the acarbose possesses significant efficacy in binding at the catalytic site of H. pylori PDF. Acarbose is a FDA-approved anti-diabetic drug thus its antibacterial efficacy may be directly studied in clinical trials. Further, the in vitro and in vivo studies are needed to study the antibacterial mode of action of acarbose in physiological conditions.