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A novel series of 7-methoxytacrine (7-MEOTA)-donepezil like compounds was synthesized and tested for their ability to inhibit electric eel acetylcholinesterase (EeAChE), human recombinant AChE (hAChE), equine serum butyrylcholinesterase (eqBChE) and human plasmatic BChE (hBChE). New hybrids consist of a 7-MEOTA unit, representing less toxic tacrine (THA) derivative, connected with analogues of N-benzylpiperazine moieties mimicking N-benzylpiperidine fragment from donepezil. 7-MEOTA-donepezil like compounds exerted mostly non-selective profile in inhibiting cholinesterases of different origin with IC50 ranging from micromolar to sub-micromolar concentration scale. Kinetic analysis confirmed mixed-type inhibition presuming that these inhibitors are capable to simultaneously bind peripheral anionic site (PAS) as well as catalytic anionic site (CAS) of AChE. Molecular modeling studies and QSAR studies were performed to rationalize studies from in vitro. Overall, 7-MEOTA-donepezil like derivatives can be considered as interesting candidates for Alzheimer's disease treatment.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- butyrylcholinesterasa krev metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- Electrophorus MeSH
- indany chemie farmakologie MeSH
- koně MeSH
- kvantitativní vztahy mezi strukturou a aktivitou * MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- piperidiny chemie farmakologie MeSH
- rekombinantní proteiny metabolismus MeSH
- takrin analogy a deriváty chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The present work aimed to compare the small, neutral and monoaromatic oxime, isatin-3-oxime (isatin-O), to the commercial ones, pralidoxime (2-PAM) and obidoxime, in a search for a new potential reactivator for acetylcholinesterase (AChE) inhibited by the pesticide paraoxon (AChE/POX) as well as a novel potential scaffold for further synthetic modifications. The multicriteria decision methods (MCDM) allowed the identification of the best docking poses of those molecules inside AChE/POX for further molecular dynamic (MD) studies, while Ellman's modified method enabled in vitro inhibition and reactivation assays. In corroboration with the theoretical studies, our experimental results showed that isatin-O have a reactivation potential capable of overcoming 2-PAM at the initial moments of the assay. Despite not achieving better results than obidoxime, this molecule is promising for being an active neutral oxime with capacity of crossing the blood⁻brain barrier (BBB), to reactivate AChE/POX inside the central and peripheral nervous systems. Moreover, the fact that isatin-O can also act as anticonvulsant makes this molecule a possible multipotent reactivator. Besides, the MCDM method showed to be an accurate method for the selection of the best docking poses generated in the docking studies.
- MeSH
- cholinesterasové inhibitory farmakologie MeSH
- erytrocyty účinky léků enzymologie MeSH
- molekulární modely * MeSH
- molekulární struktura MeSH
- oximy chemie farmakologie MeSH
- paraoxon chemie farmakologie MeSH
- reaktivátory cholinesterázy chemie farmakologie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- Publikační typ
- časopisecké články MeSH
Poisoning with organophosphorus compounds used as pesticides or misused as chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase and butyrylcholinesterase, which causes overstimulation of the cholinergic system and often leads to serious injury or death. Treatment of organophosphorus poisoning involves, among other strategies, the administration of oxime compounds. Oximes reactivate cholinesterases by breaking the covalent bond between the serine residue from the enzyme active site and the phosphorus atom of the organophosphorus compound. Although the general mechanism of reactivation has been known for years, the exact molecular aspects determining the efficiency and selectivity of individual oximes are still not clear. This hinders the development of new active compounds. In our research, using relatively simple and widely available molecular docking methods, we investigated the reactivation of acetyl- and butyrylcholinesterase blocked by sarin and tabun. For the selected oximes, their binding modes at each step of the reactivation process were identified. Amino acids essential for effective reactivation and those responsible for the selectivity of individual oximes against inhibited acetyl- and butyrylcholinesterase were identified. This research broadens the knowledge about cholinesterase reactivation and demonstrates the usefulness of molecular docking in the study of this process. The presented observations and methods can be used in the future to support the search for new effective reactivators.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- aktivace enzymů MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory farmakologie MeSH
- fosfor chemie MeSH
- katalytická doména MeSH
- konformace proteinů MeSH
- kvantová teorie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- myši MeSH
- organofosfáty chemie MeSH
- oximy chemie MeSH
- proteosyntéza MeSH
- reaktivátory cholinesterázy farmakologie MeSH
- sarin chemie MeSH
- shluková analýza MeSH
- simulace molekulového dockingu * MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Aflatoxins are secondary metabolites of the fungi Aspergillus flavus and A. parasiticus. Among them, aflatoxin B1 (AFB1) is the most frequent type in nature and the most carcinogenic for mammals. It can contaminate many kinds of food like seeds, oil, olives, milk, dairy products, corn and meat, causing acute and chronic damages to the organism, especially in the liver, being, for this reason, considered highly hepatotoxic. AFB1 is also a mixed inhibitor of the enzyme acetylcholinesterase (AChE). This fact, together with its high toxicity and carcinogenicity, turns AFB1 into a potential chemical and biological warfare agent, as well as its metabolites. In order to investigate this, we performed inedited molecular modeling studies on the interactions of AFB1 and its metabolites inside the peripheral anionic site of human AChE (HssAChE), to verify their stability, suggest the preferential ways of inhibition, and compare their behavior to each other. Our results suggest that all metabolites can be better inhibitors of HssAChE than AFB1 and that AFBO and AFM1, the most toxic and carcinogenic metabolites of AFB1, are also the most effective HssAChE inhibitors among the AFB1 metabolites. Communicated by Ramaswamy H. Sarma.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- aflatoxin B1 chemie metabolismus MeSH
- anionty MeSH
- lidé MeSH
- ligandy MeSH
- metabolom * MeSH
- molekulární modely * MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- termodynamika MeSH
- vodíková vazba MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In this study, we have carried out a combined experimental and computational investigation to elucidate several bred-in-the-bone ideas standing out in rational design of novel cationic surfactants as antibacterial agents. Five 3-hydroxypyridinium salts differing in the length of N-alkyl side chain have been synthesized, analyzed by high performance liquid chromatography, tested for in vitro activity against a panel of pathogenic bacterial and fungal strains, computationally modeled in water by a SCRF B3LYP/6-311++G(d,p) method, and evaluated by a systematic QSAR analysis. Given the results of this work, the hypothesis suggesting that higher positive charge of the quaternary nitrogen should increase antimicrobial efficacy can be rejected since 3-hydroxyl group does increase the positive charge on the nitrogen but, simultaneously, it significantly derogates the antimicrobial activity by lowering the lipophilicity and by escalating the desolvation energy of the compounds in comparison with non-hydroxylated analogues. Herein, the majority of the prepared 3-hydroxylated substances showed notably lower potency than the parent pyridinium structures, although compound 8 with C12 alkyl chain proved a distinctly better antimicrobial activity in submicromolar range. Focusing on this anomaly, we have made an effort to reveal the reason of the observed activity through a molecular dynamics simulation of the interaction between the bacterial membrane and compound 8 in GROMACS software.
- MeSH
- antibakteriální látky chemie farmakologie toxicita MeSH
- Bacteria účinky léků MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- houby účinky léků MeSH
- hydrofobní a hydrofilní interakce MeSH
- křečci praví MeSH
- kvantitativní vztahy mezi strukturou a aktivitou * MeSH
- molekulární konformace MeSH
- pyridiny chemie farmakologie toxicita MeSH
- simulace molekulární dynamiky * MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Aflatoxin M1 (AFM1) is a mycotoxin produced by Aspergillus fungi and found in contaminated milk, breastfeed and dairy products, being highly toxic and carcinogenic to humans and other mammalian species. It is also produced in the human body as a metabolite of aflatoxin B1 (AFB1), one of the most toxic natural products known. Previous studies have shown that AFM1 is a potential inhibitor of the enzyme acetylcholinesterase (AChE), and therefore, a potential neurotoxic agent. In this work, surface screening (SS) and molecular dynamics (MD) simulation on human acetylcholinesterase AChE (HssAChE) were performed to corroborate literature data regarding preferential binding sites and type of inhibition. Also, an inedited theoretical study on the interactions of AFM1 with human butyrylcholinesterase (HssBChE) was performed. In vitro inhibition tests on both enzymes were done to support theoretical results. MD simulations suggested the catalytic anionic site of HssAChE as the preferential binding site for AFM1 and also that this metabolite is not a good inhibitor of HssBChE, corroborating previous studies. In vitro assays also corroborated molecular modeling studies by showing that AFM1 did not inhibit BChE and was able to inhibit AChE, although not as much as AFB1.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- aflatoxin B1 chemie metabolismus MeSH
- aflatoxin M1 chemie metabolismus MeSH
- Aspergillus metabolismus MeSH
- butyrylcholinesterasa chemie metabolismus MeSH
- katalytická doména MeSH
- lidé MeSH
- povrchové vlastnosti MeSH
- simulace molekulární dynamiky MeSH
- termodynamika MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
The compounds 7-chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one (5) and 5-[-7-chloro-2,4-dioxo-1H, 2H, 3H, 4H, 5H-chromeno[2,3-d]pyrimidin-5-yl)]-1,3-diazinane-2,4,6-trione (7), were synthesized from dimedone and barbituric acid and had their three-dimensional structures and precise chemical shifts assignments obtained by Nuclear Magnetic Resonance (NMR) from 1H, 13C, APT, COSY, HSQC, and HMBC spectra. Additional HOMO-LUMO DFT calculations corroborated the NMR results and pointed to the most stable stereoisomers of each compound. Besides, further docking and molecular dynamic studies suggest that the stereoisomers (9S)-7-chloro-9-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one, and 5-[(5S)-7-chloro-2,4-dioxo-1H, 2H, 3H, 4H, 5H-chromeno[2,3-d]pyrimidin-5-yl)]-1,3-diazinane-2,4,6-trione of these compounds may act as DNA intercalators and qualify as potential leads for the development of new anticancer drugs.Communicated by Ramaswamy H. Sarma.
A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- amantadin chemická syntéza chemie farmakologie terapeutické užití MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie terapeutické užití MeSH
- dimerizace * MeSH
- enzymatické testy MeSH
- inhibiční koncentrace 50 MeSH
- lidé MeSH
- molekulární modely * MeSH
- referenční standardy MeSH
- simulace molekulového dockingu MeSH
- takrin analogy a deriváty chemická syntéza chemie farmakologie terapeutické užití MeSH
- thiomočovina chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Structure and behavior of amphiphilogel nanoparticles as a drug carriers for cyclosporine A (CsA) have been studied by the molecular modeling using empirical force field. Five atomistic models of a gel-based emulsions (GEM) with various gel compositions have been investigated in order to find a system most similar to a sixth atomistic model of self-microemulsifying drug delivery system (SMEDDS) taken as an exemplar of CsA delivery system. Structural parameters and energy characteristics (i.e. non-bond interaction energy between CsA and whole remaining components of a gel nanoparticle, CsA/gel nanoparticle intermolecular non-bond interaction energy, CsA-gel molecule pair interaction energy, volume fraction, concentration profiles and number of pervaded water molecules) of these six models in a waterless form and in a water containing form have been studied in dependence on the composition. The Flory-Huggins theory as implemented in the Accelrys Materials Studio 4.2 modeling environment was used to study the pair interactions of cyclosporine A with various types of surfactants. Structural parameters and energy characteristics of all systems have been compared and one composition was selected as a very promising for further experimental study.
- MeSH
- aplikace orální MeSH
- cyklosporin aplikace a dávkování chemie MeSH
- emulze MeSH
- gely MeSH
- imunosupresiva aplikace a dávkování chemie MeSH
- molekulární modely MeSH
- nanočástice MeSH
- povrchově aktivní látky chemie MeSH
- systémy cílené aplikace léků MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
