title: Molecular dynamics of sialic acid analogues complex with cholera toxin and DFT optimization of ethylene glycol-mediated zinc nanocluster conjugation.
abstract: Cholera is an infectious disease caused by cholera toxin (CT) protein of bacterium Vibrio cholerae. A sequence of sialic acid (N-acetylneuraminic acid, NeuNAc or Neu5Ac) analogues modified in its C-5 position is modelled using molecular modelling techniques and docked against the CT followed by molecular dynamics simulations. Docking results suggest better binding affinity of NeuNAc analogue towards the binding site of CT. The NeuNAc analogues interact with the active site residues GLU:11, TYR:12, HIS:13, GLY:33, LYS:34, GLU:51, GLN:56, HIE:57, ILE:58, GLN:61, TRP:88, ASN:90 and LYS:91 through intermolecular hydrogen bonding. Analogues N-glycolyl-NeuNAc, N-Pentanoyl-NeuNAc and N-Propanoyl-NeuNAc show the least XPGscore (docking score) of -9.90, -9.16, and -8.91, respectively, and glide energy of -45.99, -42.14 and -41.66 kcal/mol, respectively. Stable nature of CT-N-glycolyl-NeuNAc, CT-N-Pentanoyl-NeuNAc and CT-N-Propanoyl-NeuNAc complexes was verified through molecular dynamics simulations, each for 40 ns using the software Desmond. All the nine NeuNAc analogues show better score for drug-like properties, so could be considered as suitable candidates for drug development for cholera infection. To improve the enhanced binding mode of NeuNAc analogues towards CT, the nine NeuNAc analogues are conjugated with Zn nanoclusters through ethylene glycol (EG) as carriers. The NeuNAc analogues conjugated with EG-Zn nanoclusters show better binding energy towards CT than the unconjugated nine NeuNAc analogues. The electronic structural optimization of EG-Zn nanoclusters was carried out for optimizing their performance as better delivery vehicles for NeuNAc analogues through density functional theory calculations. These sialic acid analogues may be considered as novel leads for the design of drug against cholera and the EG-Zn nanocluster may be a suitable carrier for sialic acid analogues.
authors.affiliation: a Department of Nano Science and Technology , Tamil Nadu Agricultural University , Coimbatore 641003 , Tamil Nadu , India.
authors.forename: D Jeya Sundara
authors.initials: DJ
authors.lastname: Sharmila
authors.affiliation: b Department of Bioinformatics , Karunya University , Karunya Nagar, Coimbatore 641 114 , Tamil Nadu , India.
authors.forename: J
authors.initials: J
authors.lastname: Jino Blessy
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002772:Cholera Toxin / Q000737:chemistry*; D019855:Ethylene Glycol / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D019158:N-Acetylneuraminic Acid / Q000737:chemistry*; D011485:Protein Binding; D015032:Zinc / Q000737:chemistry*
chemical_list: D008024:Ligands; D002772:Cholera Toxin; D019855:Ethylene Glycol; D019158:N-Acetylneuraminic Acid; D015032:Zinc
keywords: cholera toxin; drug-like activity; ethylene glycol – zn nanoclusters; molecular docking; molecular dynamic simulation; sialic acid (n-acetylneuraminic acid)