title: Allosteric site-mediated active site inhibition of PBP2a using Quercetin 3-O-rutinoside and its combination.
abstract: Recent crystallographic study revealed the involvement of allosteric site in active site inhibition of penicillin binding protein (PBP2a), where one molecule of Ceftaroline (Cef) binds to the allosteric site of PBP2a and paved way for the other molecule (Cef) to bind at the active site. Though Cef has the potency to inhibit the PBP2a, its adverse side effects are of major concern. Previous studies have reported the antibacterial property of Quercetin derivatives, a group of natural compounds. Hence, the present study aims to evaluate the effect of Quercetin 3-o-rutinoside (Rut) in allosteric site-mediated active site inhibition of PBP2a. The molecular docking studies between allosteric site and ligands (Rut, Que, and Cef) revealed a better binding efficiency (G-score) of Rut (-7.790318) and Cef (-6.194946) with respect to Que (-5.079284). Molecular dynamic (MD) simulation studies showed significant changes at the active site in the presence of ligands (Rut and Cef) at allosteric site. Four different combinations of Rut and Cef were docked and their G-scores ranged between -6.320 and -8.623. MD studies revealed the stability of the key residue (Ser403) with Rut being at both sites, compared to other complexes. Morphological analysis through electron microscopy confirmed that combination of Rut and Cefixime was able to disturb the bacterial cell membrane in a similar fashion to that of Rut and Cefixime alone. The results of this study indicate that the affinity of Rut at both sites were equally good, with further validations Rut could be considered as an alternative for inhibiting MRSA growth.
authors.affiliation: a Centre for Bioinformatics, School of Life Sciences , Pondicherry University , R. V. Nagar Kalapet, Pondicherry 605014 , India.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Rani
authors.affiliation: a Centre for Bioinformatics, School of Life Sciences , Pondicherry University , R. V. Nagar Kalapet, Pondicherry 605014 , India.|b Centre for Advanced Study in Crystallography and Biophysics , University of Madras , Tamilnadu , India.
authors.forename: Saravanan
authors.initials: S
authors.lastname: Vijayakumar
authors.affiliation: a Centre for Bioinformatics, School of Life Sciences , Pondicherry University , R. V. Nagar Kalapet, Pondicherry 605014 , India.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: P T V
authors.affiliation: c Department of Botany , Sethupathy Government Arts and Science College, Alagappa University , Ramanathpuram , Tamil Nadu , India.
authors.forename: Annamalai
authors.initials: A
authors.lastname: Arunachalam
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D005960:Glucosides / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D005960:Glucosides; D008024:Ligands; D046915:Penicillin-Binding Proteins; D011794:Quercetin
keywords: MRSA; PBP2a; Quercetin 3-o-rutinoside; SEM and TEM; molecular docking; simulation