molecular modeling Dotaz Zobrazit nápovědu

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A simple molecular modeling method for the characterization of polymeric drug carriers is presented. Six biodegradable polymers have been investigated as drug carriers using molecular simulations: l-polylactide, d-polylactide, chitosan, polyglycolic acid, polyethylene glycol and cellulose. Cyclosporine A has been chosen as a model drug substance. Classical molecular dynamics and docking calculations were employed to model and predict polymer-drug interactions. These interactions have been analyzed by non-bond interaction energy and interaction parameter calculated using Flory-Huggins theory. Flexibility of polymer chains has been characterized by the change of gyration radius along the molecular dynamics trajectory. The relationship between mixing energy, chain length and chain flexibility has been revealed for each polymer/drug system.

Článek online

Interactions of human butyrylcholinesterase with phenylvalerate and acetylthiocholine as substrates and inhibitors: kinetic and molecular modeling approaches

... (PV) is a substrate for measuring the PVase activity of neuropathy target esterase (NTE), a key molecular ...

Archives of toxicology. 2019 ; 93 (5) : 1281-1296. [pub] 20190315

Arch Toxicol
ISSN 1432-0738
Medvik
Zdroj

Phenyl valerate (PV) is a substrate for measuring the PVase activity of neuropathy target esterase (NTE), a key molecular event of organophosphorus-induced delayed neuropathy. A protein with PVase activity in chicken (model for delayed neurotoxicity) was identified as butyrylcholinesterase (BChE). Purified human butyrylcholinesterase (hBChE) showed PVase activity with a similar sensitivity to inhibitors as its cholinesterase (ChE) activity. Further kinetic and theoretical molecular simulation studies were performed. The kinetics did not fit classic competition models among substrates. Partially mixed inhibition was the best-fitting model to acetylthiocholine (AtCh) interacting with PVase activity. ChE activity showed substrate activation, and non-competitive inhibition was the best-fitting model to PV interacting with the non-activated enzyme and partial non-competitive inhibition was the best fitted model for PV interacting with the activated enzyme by excess of AtCh. The kinetic results suggest that other sites could be involved in those activities. From the theoretical docking analysis, we deduced other more favorable sites for binding PV related with Asn289 residue, situated far from the catalytic site ("PV-site"). Both substrates acethylcholine (ACh) and PV presented similar docking values in both the PV-site and catalytic site pockets, which explained some of the observed substrate interactions. Molecular dynamic simulations based on the theoretical structure of crystallized hBChE were performed. Molecular modeling studies suggested that PV has a higher potential for non-competitive inhibition, being also able to inhibit the hydrolysis of ACh through interactions with the PV-site. Further theoretical studies also suggested that PV could yet be able to promote competitive inhibition. We concluded that the kinetic and theoretical studies did not fit the simple classic competition among substrates, but were compatible with the interaction with two different binding sites.

Časopis

Journal of molecular recognition

London : Heyden & Son, 1988- | Bognor Regis [West Sussex] : John Wiley & Sons

sv.

Konspekt
Biochemie. Molekulární biologie. Biofyzika
NLK Obory
biologie
biochemie

Článek online

Low-molecular weight inhibitory factor released in vitro by murine l5178y leukemic cells

Neoplasma. 1987 ; Roč. 34 (č. 5) : S. 513-521.

ISSN 0028-2685
Medvik
Zdroj

Článek online

Enzymatic characterization and molecular modeling of an evolutionarily interesting fungal β-N-acetylhexosaminidase

... understand these features, we performed isolation, biochemical and enzymological characterization, molecular ...

The FEBS journal. 2011 ; 278 (14) : 2469-84. [pub] 20110601

FEBS J
ISSN 1742-4658
Medvik
Zdroj

Fungal β-N-acetylhexosaminidases are inducible extracellular enzymes with many biotechnological applications. The enzyme from Penicillium oxalicum has unique enzymatic properties despite its close evolutionary relationship with other fungal hexosaminidases. It has high GalNAcase activity, tolerates substrates with the modified N-acyl group better and has some other unusual catalytic properties. In order to understand these features, we performed isolation, biochemical and enzymological characterization, molecular cloning and molecular modelling. The native enzyme is composed of two catalytic units (65 kDa each) and two propeptides (15 kDa each), yielding a molecular weight of 160 kDa. Enzyme deglycosylated by endoglycosidase H had comparable activity, but reduced stability. We have cloned and sequenced the gene coding for the entire hexosaminidase from P. oxalicum. Sufficient sequence identity of this hexosaminidase with the structurally solved enzymes from bacteria and humans with complete conservation of all catalytic residues allowed us to construct a molecular model of the enzyme. Results from molecular dynamics simulations and substrate docking supported the experimental kinetic and substrate specificity data and provided a molecular explanation for why the hexosaminidase from P. oxalicum is unique among the family of fungal hexosaminidases.

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