Malyngamide C a potential inhibitor of protein synthesis Machinery targeting peptide deformylase enzyme

Abstract

Due to the rising incidence of antibiotic-resistant and bacterial illnesses, new therapeutic drugs are essential to target vital bacterial enzymes. Peptide deformylase is an attractive antibacterial target because it plays a pivotal role in protein synthesis. The present study was guided to identify the potential inhibitors of peptide deformylase (PDF), viz., computational methods such as molecular docking, molecular dynamics (MD) simulations, thermodynamic stability, free energy calculations, and ADMET analysis.

Here we observed the toxicity profile and drug-likeness of the in-house cyanopeptides database. The malyngamide C showed good oral bioavailability. Molecular docking experiments revealed that malyngamide C showed a better binding affinity of −8.81 kcal/mol than reference actinonin −7.08 kcal/mol. Next, MD simulations revealed that malyngamide C, tumonoic acid A, borophycin, and actinonin were found stable in the binding pocket of PDF observed for 300 ns. The binding posture was well-retained, with negligible RMSD, and found within permissible limits observed throughout the simulations. From the MM/PBSA calculations, the free binding energy of malyngamide C was found to be −145.281 kJ/mol, significantly exceeding other selected molecules, including actinonin. The malyngamide C could be a lead antibacterial candidate with a good safety profile. These computational findings strongly support its experimental validation and further clinical investigations as a novel antibacterial agent to combat drug-resistant bacterial infections.