In silico designing and molecular docking of a potent analog against Staphylococcus aureus porphobilinogen synthase

Abstract

Background:The emergence of multidrug-resistant strains of Staphylococcus aureus, there is an urgent need for the development of new antimicrobials which are narrow and pathogen specific.Aim:In this context, the present study is aimed to have a control on the staphylococcal infections by targeting the unique and essential enzyme; porphobilinogen synthase (PBGS) catalyzes the condensation of two molecules of δ-aminolevulinic acid, an essential step in the tetrapyrrole biosynthesis. Hence developing therapeutics targeting PBGS will be the promising choice to control and manage the staphylococcal infections. 4,5-dioxovalerate (DV) is known to inhibit PBGS.Materials and Methods:In view of this, in this study, novel dioxovalerate derivatives (DVDs) molecules were designed so as to inhibit PBGS, a potential target of S. aureus and their inhibitory activity was predicted using molecular docking studies by molecular operating environment. The 3D model of PBGS was constructed using Chlorobium vibrioform (Protein Data Bank 1W1Z) as a template by homology modeling method.Results:The built structure was close to the crystal structure with Z score − 8.97. Molecular docking of DVDs into the S. aureus PBGS active site revealed that they are showing strong interaction forming H-bonds with the active sites of K248 and R217. The ligand–receptor complex of DVD13 showed a best docking score of − 14.4555 kcal/mol among DV and all its analogs while the substrate showed docking score of − 13.0392 kcal/mol showing interactions with S199, K217 indicating that DVD13 can influence structural variations on the enzyme and thereby inhibiting the enzyme.Conclusion:The substrate analog DVD13 is showing significant interactions with active site of PBGS and it may be used as a potent inhibitor to control S. aureus infections.

Novel mutations in the kinase domain of BCR-ABL gene causing imatinib resistance in chronic myeloid leukemia patients

“…The ABL structure was retrieved from the Protein Data Bank (PDB ID: 1OPL) (http://www.rcsb.org/pdb/explore/explore.do?structureId=1OPL) with the resolution of 3.42 Å and was loaded into the MOE working environment ignoring all water molecules and heteroatoms. The structure was subjected to protonation followed by energy minimization under MMFF94x force field (Merck Molecular Force Field) 36,37 to an RMSD of 0.05 where the implicit solvated environment was specified and the stabilized conformation was saved in PDB format. The mutations identified in the ABL gene were introduced individually in the wild-type energy minimized ABL protein, the resultant structures was again subjected to energy minimization.…”

“…The mutations identified in the ABL gene were introduced individually in the wild-type energy minimized ABL protein, the resultant structures was again subjected to energy minimization. The energy minimization was done with the same parameter set and the stabilized conformation of the mutated ABL structures was saved individually in PDB file 36,37 .…”

The Se…S/N interactions as a possible mechanism of δ-aminolevulinic acid dehydratase enzyme inhibition by organoselenium compounds: A computational study

“…However, the Mg 2+ is essential to enzyme function, as observed in E. coli, Bradyrhizobium japonicum, Pseudomonas aeruginosa, and P. sativum, due to the H-bonding network around this metal ion maintaining the quaternary structure of δ-AlaD [13][14][15]86]. This difference in the active site of δ-AlaD from different species must be taken into account in the design of selective inhibitors with useful applications, such as in the case of δ-AlaD from Wolbachia [91-93] and Staphylococcus aureus [94]. Moreover, due to the similarity of the active site from δ-AlaD of the group B, the use of plant δ-AlaD (such as cucumber) can provide a simple, practical and cheap in vitro assay to find new selective inhibitors.…”

In Staphylococcus aureus the regulation of pyruvate kinase activity by serine/threonine protein kinase favors biofilm formation

“…The most common form of allosteric regulation for PK is its upregulation by FBP, which increases the affinity and reduces the co-operativity of substrate binding which also depends on bound divalent cations in the active site. Here bound substrate and metal ions increases affinity of FBP for the allosteric site (Bond et al 2000 ; Zoraghi et al 2010 , 2011a , b ; Kumar et al 2014 ). ATP, Alanine, and phenylalanine become negative allosteric inhibitors for PK and serves as a switch between the glycolytic and gluconeogenic pathways.…”