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1.
Chem Biol Interact ; 385: 110734, 2023 Nov 01.
Article in English | MEDLINE | ID: mdl-37788753

ABSTRACT

Acetylcholinesterase (AChE, EC 3.1.1.7) reactivators (2-PAM, trimedoxime, obidoxime, asoxime) have become an integral part of antidotal treatment in cases of nerve agent and organophosphorus (OP) pesticide poisonings. They are often referred to as specific antidotes due to their ability to restore AChE function when it has been covalently inhibited by an OP compound. Currently available commercial reactivators exhibit limited ability to penetrate the blood-brain barrier, where reactivation of inhibited AChE is crucial. Consequently, there have been numerous efforts to discover more brain-penetrating AChE reactivators. In this study, we examined a derivative of 2-PAM designed to possess increased lipophilicity. This enhanced lipophilicity was achieved through the incorporation of a benzyl group into its molecular structure. Initially, a molecular modeling study was conducted, followed by a comparison of its reactivation efficacy with that of 2-PAM against 10 different AChE inhibitors in vitro. Unfortunately, this relatively significant structural modification of 2-PAM resulted in a decrease in its reactivation potency. Consequently, this derivative cannot be considered as a broad-spectrum AChE reactivator.


Subject(s)
Cholinesterase Reactivators , Organophosphate Poisoning , Humans , Cholinesterase Reactivators/chemistry , Acetylcholinesterase/metabolism , Pralidoxime Compounds/pharmacology , Antidotes/pharmacology , Oximes/pharmacology , Oximes/chemistry , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/metabolism
2.
Chem Biol Interact ; 382: 110619, 2023 Sep 01.
Article in English | MEDLINE | ID: mdl-37406983

ABSTRACT

The Near Attack Conformation (NAC) approach states that the efficiency of an enzyme-catalyzed reaction depends on the prior attainment of optimal conditions for substrate atom organization and positioning for bond formation. These conditions are prerequisites for the transition state (TS) in which the involved atoms are within the van der Waals range of contact and positioned at an angle similar to that achieved after bond formation. The successful application of this approach to investigate the reactivation mechanism of acetylcholinesterase inhibited by nerve agents has contributed to a better understanding of this mechanism and demonstrated consistent corroboration with experimental data. In this article, we summarize the accomplishments achieved thus far and outline future perspectives.


Subject(s)
Cholinesterase Reactivators , Cholinesterase Reactivators/pharmacology , Cholinesterase Reactivators/chemistry , Acetylcholinesterase/chemistry , Oximes/chemistry , Cholinesterase Inhibitors/pharmacology
4.
Sci Rep ; 11(1): 9999, 2021 05 11.
Article in English | MEDLINE | ID: mdl-33976335

ABSTRACT

The availability of well-assembled genome sequences and reduced sequencing costs have enabled the resequencing of many additional accessions in several crops, thus facilitating the rapid discovery and development of simple sequence repeat (SSR) markers. Although the genome sequence of inbred spinach line Sp75 is available, previous efforts have resulted in a limited number of useful SSR markers. Identification of additional polymorphic SSR markers will support genetics and breeding research in spinach. This study aimed to use the available genomic resources to mine and catalog a large number of polymorphic SSR markers. A search for SSR loci on six chromosome sequences of spinach line Sp75 using GMATA identified a total of 42,155 loci with repeat motifs of two to six nucleotides in the Sp75 reference genome. Whole-genome sequences (30x) of additional 21 accessions were aligned against the chromosome sequences of the reference genome and in silico genotyped using the HipSTR program by comparing and counting repeat numbers variation across the SSR loci among the accessions. The HipSTR program generated SSR genotype data were filtered for monomorphic and high missing loci, and a final set of the 5986 polymorphic SSR loci were identified. The polymorphic SSR loci were present at a density of 12.9 SSRs/Mb and were physically mapped. Out of 36 randomly selected SSR loci for validation, two failed to amplify, while the remaining were all polymorphic in a set of 48 spinach accessions from 34 countries. Genetic diversity analysis performed using the SSRs allele score data on the 48 spinach accessions showed three main population groups. This strategy to mine and develop polymorphic SSR markers by a comparative analysis of the genome sequences of multiple accessions and computational genotyping of the candidate SSR loci eliminates the need for laborious experimental screening. Our approach increased the efficiency of discovering a large set of novel polymorphic SSR markers, as demonstrated in this report.


Subject(s)
Genome, Plant , Microsatellite Repeats , Polymorphism, Genetic , Spinacia oleracea/genetics , Chromosomes, Plant , Computer Simulation , Whole Genome Sequencing
5.
Biomolecules ; 10(2)2020 01 27.
Article in English | MEDLINE | ID: mdl-32012780

ABSTRACT

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.


Subject(s)
Acetylcholinesterase/drug effects , Organothiophosphorus Compounds/pharmacology , Pralidoxime Compounds/pharmacology , Acetylcholinesterase/chemistry , Catalytic Domain , Humans , Molecular Conformation , Molecular Dynamics Simulation , Pralidoxime Compounds/chemistry , Protons , Quantum Theory , Serine/chemistry
6.
J Enzyme Inhib Med Chem ; 34(1): 1018-1029, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31074292

ABSTRACT

7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.


Subject(s)
Cholinesterase Inhibitors/pharmacology , Obidoxime Chloride/pharmacology , Organothiophosphorus Compounds/pharmacology , Oximes/pharmacology , Pralidoxime Compounds/pharmacology , Pyridines/pharmacology , Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Obidoxime Chloride/chemistry , Organothiophosphorus Compounds/chemistry , Oximes/chemistry , Pralidoxime Compounds/chemistry , Pyridines/chemistry , Structure-Activity Relationship
7.
Chem Biol Interact ; 307: 195-205, 2019 Jul 01.
Article in English | MEDLINE | ID: mdl-31121152

ABSTRACT

The novel prophylactic agent 7-methoxytacrine-4-pyridinealdoxime is a hybrid compound formerly designed to keep acetylcholinesterase resistant to organophosphates by reactivating it in case of intoxication by such inhibitors. In rational design, a 5-carbon length-spacer hybrid compound was synthesized to evaluate its inhibitory and reactivation capabilities. In this work, theoretical results were achieved through molecular modelling techniques, taking for granted the enzymatic reactivation reaction through nucleophilic substitution. Based on the near attack conformation approach, docking studies were performed to assess the spacer-length from 1 to 10 carbons long of a series of analogues of 7-methoxytacrine-4-pyridinealdoxime. Consequently, the hybrids with length-spacer of 4 and 5 carbons long were the best assessed and subsequently subjected to further molecular dynamics simulations, complemented by Poisson-Boltzmann surface area calculations. As a result, intermolecular interactions with the different binding sites inside human acetylcholinesterase were elucidated. Besides, thermodynamics and kinetics concepts pointed to the 4-carbon linker as optimum for enzymatic reactivation. Further studies, based on quantum mechanics in conjunction with molecular mechanics, were recommended to the presented near attack conformations to achieve more thermodynamics results between the hybrids with 4- and 5-carbon linkers, like values of activation energy for the reactivation reaction. All of those in silico evaluations could be considered as a set of tools for theoretically investigate novel enzymatic reactivators with different shape of spacers.


Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Organothiophosphorus Compounds/chemistry , Tacrine/analogs & derivatives , Acetylcholinesterase/chemistry , Binding Sites , Cholinesterase Inhibitors/metabolism , Humans , Ligands , Molecular Docking Simulation , Organothiophosphorus Compounds/metabolism , Oximes/chemistry , Protein Structure, Tertiary , Tacrine/chemistry , Tacrine/metabolism , Thermodynamics
8.
Molecules ; 23(5)2018 05 07.
Article in English | MEDLINE | ID: mdl-29735900

ABSTRACT

Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called "oximes") depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.


Subject(s)
Acetylcholinesterase/chemistry , Antidotes/chemical synthesis , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Cholinesterase Reactivators/chemical synthesis , Insecticides/antagonists & inhibitors , Oximes/chemical synthesis , Paraoxon/antagonists & inhibitors , Antidotes/pharmacology , Cholinesterase Reactivators/pharmacology , Enzyme Assays , Erythrocytes/drug effects , Erythrocytes/enzymology , Humans , Insecticides/chemistry , Insecticides/toxicity , Molecular Docking Simulation , Obidoxime Chloride/chemistry , Obidoxime Chloride/pharmacology , Oximes/pharmacology , Paraoxon/chemistry , Paraoxon/toxicity , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Structure-Activity Relationship , Thermodynamics
9.
J Biomol Struct Dyn ; 36(13): 3444-3452, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29019446

ABSTRACT

The oximes 4-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HI-6) and 3-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HS-6) are isomers differing from each other only by the position of the carbamoyl group on the pyridine ring. However, this slight difference was verified to be responsible for big differences in the percentual of reactivation of acetylcholinesterase (AChE) inhibited by the nerve agents tabun, sarin, cyclosarin, and VX. In order to try to find out the reason for this, a computational study involving molecular docking, molecular dynamics, and binding energies calculations, was performed on the binding modes of HI-6 and HS-6 on human AChE (HssAChE) inhibited by those nerve agents.


Subject(s)
Acetylcholinesterase/metabolism , Chemical Warfare Agents/chemistry , Cholinesterase Inhibitors/chemistry , Nerve Agents/chemistry , Oximes/metabolism , Pralidoxime Compounds/metabolism , Pyridinium Compounds/metabolism , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Organophosphates/chemistry , Organophosphorus Compounds/chemistry , Organothiophosphorus Compounds/chemistry , Sarin/chemistry
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