An explorative study on diarylquinoline-based inhibitor targeting Enterococcus faecium MurF
- PDF / 2,095,325 Bytes
- 11 Pages / 595.276 x 790.866 pts Page_size
- 27 Downloads / 168 Views
ORIGINAL RESEARCH
An explorative study on diarylquinoline-based inhibitor targeting Enterococcus faecium MurF Mohammed Afzal Azam 1
&
Vyshaag Chembakam veetil Manoj 1
Received: 13 May 2020 / Accepted: 18 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Enterococcus faecium MurF (EfMurF) enzyme catalyzes the addition of D-alanyl-D-alanine to form murein UDP-Nacetylmuramoyl-pentapeptide. This is the last cytoplasmic step of peptidoglycan synthesis and is essential for bacterial cell wall integrity. Due to the specificity of D-amino acid utilization and its absence in eukaryotic counterpart, this enzyme is considered as an attractive target for new antibacterial discovery. In the present investigation, we prepared the 3D structure of the EfMurF catalytic pocket by homology modelling. A combined molecular modelling approach was used to get insight into the binding mode of diarylquinoline-based inhibitor 1 against EfMurF. In extra-precision (XP) docking, inhibitor 1 exhibited hydrogen bonding and π-π stacking interactions mainly with the residues of N-terminal and central domains. In the molecular mechanics/generalized born surface area (MM-GBSA) binding free energy calculation, Coulomb and the non-polar solvation energy terms are observed to be major contributors for the inhibitor binding. To gain further insight into the binding mode and inhibition potential, the inhibitor 1/EfMurF enzyme complex was analyzed with 100-ns molecular dynamics simulation. Based on the docking and MD results, we designed three new compounds D1-D3 with a high binding affinity against EfMurF. These three designed compounds were subjected to the XP docking and the binding free energy calculation. A 50-ns MD simulation was also performed for the D1/EfMurF complex. Keywords Enterococcus faecium . MurF inhibitor . Homology modelling . MM-GBSA . Molecular dynamics
Introduction The rapid emergence of resistance in pathogenic bacteria to known antibiotics has led to an increased demand for the d e v e l o p m e n t o f ne w a n t i b a c t e r i a l a g e n t s [ 1– 3 ] . Enterococcus faecium, a Gram-positive pathogen bacterium, is a causative agent for septicaemia, bacteremia, meningitis, urinary tract and wound infections with a high rate of morbidity and mortality worldwide [4]. The bacterial cell wall integrity is crucial for the survival of both Gram-positive and Gram-negative bacteria. Bacterial peptidoglycan provides Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11224-020-01622-9) contains supplementary material, which is available to authorized users. * Mohammed Afzal Azam [email protected]; [email protected] 1
Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India
rigidity and cell shape and hence is critically important for cell survival. The multi-step synthesis and incorporation of this rigid layer consist of several targets that are absent in t
Data Loading...
