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Current Medicinal Chemistry Jul 2002Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs useful in a variety of... (Review)
Review
Studies on enzyme inhibition remain an important area of pharmaceutical research since these studies have led to the discoveries of drugs useful in a variety of physiological conditions. The enzyme inhibitors can interact with enzymes and block their activity towards natural substrates. Urease inhibitors have recently attracted much attention as potential new anti-ulcer drugs. Ironically, urease was the first enzyme crystallized but its mechanism of action is still largely misunderstood. This chapter therefore reviews comprehensive developments in the field of urease inhibitors. Inhibitors of urease can be broadly classified into two categories: (1) active site directed (substrate-like), (2) mechanism-based directed. We present here the examples of selected inhibitors along with their mechanisms of action to characterize their mode of urease inhibition. The observations that urease due to its high substrate (urea) specificity can only bind to a few inhibitors with a similar binding mode as urea is also discussed. Several non-covalent interactions including hydrogen bonds and hydrophobic contacts stabilize the enzyme-inhibitor complex. Regardless of the class of compound, it is reported that only a few functional groups with electronegative atoms such as oxygen, nitrogen and sulfur act either as bidentate (mostly), tridentate (rarely), or as ligand-chelator to form octahedral complexes with two slightly distorted octahedral Ni ions of the enzyme. Bulky groups attached to the pharmacophore were found to decrease the activity of inhibitors, since the lack of a bulky attachment makes it easier for urease inhibitors to enter the substrate-binding pocket as well as avoid unfavorable steric interactions with amino acid residues in its vicinity. This review is intended to provide highlights of the inhibition of urease by hydroxamic acids (HXAs), phosphorodiamidates (PPDs), imidazoles, phosphazene and related compounds. These compounds are compared to previously reported urease inhibitors for the catalytic models proposed for urease activity. The differences in inhibition of urease activities from plants and of bacterial origin by various inhibitors and physiological implications of urease inhibition are discussed.
Topics: Abietanes; Diterpenes; Enzyme Inhibitors; Humans; Hydroxamic Acids; Imidazoles; Models, Molecular; Organophosphates; Organophosphorus Compounds; Urea; Urease
PubMed: 12132990
DOI: 10.2174/0929867023369853 -
Molecular Informatics Aug 2019In March 2018 the term Novichok (Hoвичoκ) became publically known following an attempted murder of a former Russian spy in Salisbury, UK. Novichok is the name of a...
In March 2018 the term Novichok (Hoвичoκ) became publically known following an attempted murder of a former Russian spy in Salisbury, UK. Novichok is the name of a group of nerve agents secretly produced by Russia in the later stages of the Cold War. These compounds were never declared under the Chemical Weapons Convention and very little is known about the actual identity and characteristics of these compounds. Structures of some of the Novichoks have been reported by a former Russian chemist, Vil Mirzayanov, previously working at the Russian State Scientific Research Institute of Organic Chemistry and Technology (GOSNIIOKhT). It was in this context claimed that at least two compounds of the Novichok family, known as Novichok-5 and Novichok-7 were 5-8 times more potent than the hitherto most toxic nerve agent, VX. The present study elucidates, applying a series of QSAR models toxicity, skin permeation, pharmacokinetic aspects as well as the environmental fate of a series of Novichoks. Virtually the results from the different studies related to human health point in the same direction, i. e., the Novichoks are significantly less toxic than VX and the skin permeation much lower and less efficient than observed for VX. Hence, the claim by Mirzayanov could not be substantiated.
Topics: Humans; Models, Molecular; Molecular Structure; Nerve Agents; Organophosphates; Quantitative Structure-Activity Relationship; Skin; Solubility
PubMed: 30474294
DOI: 10.1002/minf.201800106 -
Biotechnology Advances 2014The development of efficient tools is required for the eco-friendly detoxification and effective detection of neurotoxic organophosphates (OPs). Although enzymes have... (Review)
Review
The development of efficient tools is required for the eco-friendly detoxification and effective detection of neurotoxic organophosphates (OPs). Although enzymes have received significant attention as biocatalysts because of their high specific activity, the uneconomic and labor-intensive processes of enzyme production and purification make their broad use in practical applications difficult. Because whole-cell systems offer several advantages compared with free enzymes, including high stability, a reduced purification requirement, and low preparation cost, they have been suggested as promising biocatalysts for the detoxification and detection of OPs. To develop efficient whole-cell biocatalysts with enhanced activity and a broad spectrum of substrate specificity, several factors have been considered, namely the selected strains, the chosen OP-hydrolyzing enzymes, where enzymes are localized in a cell, and which enhancer will assist the expression, function, and folding of the enzyme. In this article, we review the current investigative progress in the development of engineered whole-cell biocatalysts with excellent OP-hydrolyzing activity, a broad spectrum of substrate specificity, and outstanding stability for the detoxification and detection of OPs.
Topics: Aryldialkylphosphatase; Bacteria; Biodegradation, Environmental; Bioreactors; Biotechnology; Cell Engineering; Cells, Immobilized; Organophosphates
PubMed: 24780157
DOI: 10.1016/j.biotechadv.2014.04.010 -
Environmental Science and Pollution... May 2016Organophosphorus chemicals are highly toxic molecules mainly used as pesticides. Some of them are banned warfare nerve agents. These compounds are covalent inhibitors of... (Review)
Review
Organophosphorus chemicals are highly toxic molecules mainly used as pesticides. Some of them are banned warfare nerve agents. These compounds are covalent inhibitors of acetylcholinesterase, a key enzyme in central and peripheral nervous systems. Numerous approaches, including chemical, physical, and biological decontamination, have been considered for developing decontamination methods against organophosphates (OPs). This work is an overview of both validated and emerging strategies for the protection against OP pollution with special attention to the use of decontaminating enzymes. Considerable efforts have been dedicated during the past decades to the development of efficient OP degrading biocatalysts. Among these, the promising biocatalyst SsoPox isolated from the archaeon Sulfolobus solfataricus is emphasized in the light of recently published results. This hyperthermostable enzyme appears to be particularly attractive for external decontamination purposes with regard to both its catalytic and stability properties.
Topics: Catalysis; Decontamination; Environmental Pollutants; Organophosphates; Organophosphorus Compounds; Pesticides
PubMed: 26832878
DOI: 10.1007/s11356-016-6143-1 -
Journal of the American Mosquito... Sep 2022Susceptibility to organophosphates was evaluated in 2 populations of Culex quinquefasciatus from the department of Atlantico, Colombia. Bioassays for temephos,...
Susceptibility to organophosphates was evaluated in 2 populations of Culex quinquefasciatus from the department of Atlantico, Colombia. Bioassays for temephos, malathion, and pirimiphos-methyl were performed with 3rd-stage larvae and adult females of Cx. quinquefasciatus from the municipalities of Soledad and Puerto Colombia, following the methods of the World Health Organization and Centers for Disease Control and Prevention, respectively. The median lethal concentration (LC50) and 90% lethal concentration (LC90) resistance ratios (RRLC50 and RRLC90) were determined for each insecticide in the field populations evaluated, using the Cartagena strain as the susceptible control. Relative to LC50 and LC90 of the Cartagena strain, the population from Puerto Colombia was moderately resistant to temephos (RRLC50 5.7-fold) and malathion (RRLC50 8.6-fold, RRLC90 9-fold) and susceptible to pirimiphos-methyl (RRLC50 and RRLC90 < 5-fold). The population from Soledad was susceptible to temephos and pirimiphos-methyl (RRLC50 and RRLC90 < 5-fold) and showed moderate resistance to malathion (RRLC50 7.5-fold). It is important to emphasize that routine monitoring of insecticide resistance in Cx. quinquefasciatus helps us detect resistance early and improve the effectiveness of control strategies.
Topics: Animals; Colombia; Culex; Female; Insecticide Resistance; Insecticides; Larva; Malathion; Organophosphates; Temefos
PubMed: 35839258
DOI: 10.2987/22-7058 -
Chemico-biological Interactions Nov 2016Organophosphates (OPs) are either found in nature or synthetized for use as pesticides, flame retardants, neurotoxic warfare agents or drugs (cholinergic enhancers in... (Review)
Review
Organophosphates (OPs) are either found in nature or synthetized for use as pesticides, flame retardants, neurotoxic warfare agents or drugs (cholinergic enhancers in Alzheimer's disease and myasthenia gravis, or inhibitors of lipases in metabolic diseases). Because of the central role of acetylcholinesterase cholinergic neurotransmission in humans, one of the main purposes for using OPs is inactivation of the enzyme by phosphorylation of the nucleophilic serine residue in the active center. However, hundreds of serine hydrolases are expressed in the human proteome, and many of them are potential targets for OP adduction. In this review, we first situate the α/β hydrolase fold proteins among the distinctively folded proteins known to interact with OPs, in particular the different lipases, peptidases, and enzymes hydrolyzing OPs. Second, we compile the human α/β hydrolases and review those that have been experimentally shown to interact with OPs. Among the 120 human α/β hydrolase fold proteins, 102 have a serine in the consensus GXSXG pentapeptide compatible with an active site, 6 have an aspartate or a cysteine as the active site nucleophile residue, and 12 evidently lack an active site. 76 of the 120 have been experimentally shown to bind an OP.
Topics: Biocatalysis; Enzyme Inhibitors; Humans; Hydrolases; Organophosphates; Protein Binding; Protein Structure, Secondary
PubMed: 27109753
DOI: 10.1016/j.cbi.2016.04.027 -
Analytical and Bioanalytical Chemistry Nov 2012Emerging contaminants are a broad category of chemicals, previously unknown or unrecognized as being of concern, but which, because of their potential health effects... (Review)
Review
Emerging contaminants are a broad category of chemicals, previously unknown or unrecognized as being of concern, but which, because of their potential health effects associated with human exposure, are under increasing scrutiny. To accurately measure their levels in biological matrices, specific and sensitive analytical methods have recently been developed. We have reviewed here the methods used for analysis of selected emerging organic contaminants, for example metabolites of organophosphate triesters, metabolites of new phthalates or phthalate substitutes, perchlorate, organic UV filters, and polycyclic siloxanes, in human matrices. Although the use of new techniques and approaches has been emphasized, we also acknowledge methods previously used for other contaminants and adapted for the emerging contaminants listed above. In all cases, chromatography and mass spectrometry were the techniques of choice, because of their selectivity and sensitivity for measurements at ng g(-1) levels. Critical issues and challenges have been discussed, together with recommendations for further improvement in particular cases (e.g. metabolites of phthalates or their substitutes). In particular, the use of labeled internal standards, the availability of certified reference materials, and the need for interlaboratory comparison exercises are key aspects of further development of this field of research.
Topics: Chemistry Techniques, Analytical; Chromatography, Gas; Chromatography, Liquid; Environmental Monitoring; Environmental Pollutants; Humans; Mass Spectrometry; Models, Molecular; Organophosphates; Phthalic Acids
PubMed: 22580422
DOI: 10.1007/s00216-012-6053-0 -
Chemosphere Jun 2016Due to their widespread use, organophosphate flame retardants (OPFRs) are commonly detected in various environmental matrices and have been identified as emerging... (Review)
Review
Due to their widespread use, organophosphate flame retardants (OPFRs) are commonly detected in various environmental matrices and have been identified as emerging contaminants. Considering the adverse effects of OPFRs, many researchers have paid their attention on the absorption, bioaccumulation, metabolism and internal exposure processes of OPFRs in animals and humans. In this article, we first review the diverse absorption routes of OPFRs by animals and humans (e.g., inhalation, ingestion, dermal absorption and gill absorption). Bioaccumulation and biomagnification potentials of OPFRs in different types of organisms and food webs are also summarized, based on quite limited available data and results. For metabolism, we review the Phase-I and Phase-II metabolic processes for each type of OPFRs (chlorinated OPFRs, alkyl-OPFRs and aryl-OPFRs) in the animals and humans, as well as toxicokinetic information and putative exposure biomarkers on OPFRs. Finally, we highlight gaps in our knowledge and critical directions for future internal exposure studies of OPFRs in animals and humans.
Topics: Animals; Environmental Exposure; Environmental Pollutants; Flame Retardants; Humans; Organophosphates
PubMed: 27010170
DOI: 10.1016/j.chemosphere.2016.03.003 -
Ecotoxicology and Environmental Safety Mar 2024The thyroid gland is susceptible to chemical exposure such as organophosphate insecticides (OPIs). With the ubiquitous nature of these products, humans are...
The thyroid gland is susceptible to chemical exposure such as organophosphate insecticides (OPIs). With the ubiquitous nature of these products, humans are simultaneously exposed to a multitude of chemicals. This study aimed to evaluate the association between an individual and a mixture of OPI metabolites and changes in serum thyroid hormone (TH) concentrations. The analyzed data were 1,434 participants from the United States National Health and Nutrition Examination Surveys (NHANES) cycle 2007-2008. Generalized linear model (GLM) regression, weighted quantile sum (WQS), and adaptive least absolute shrinkage and selection operator (adaptive LASSO) regression were used to investigate the associations between urinary OPI metabolites and altered serum THs. In GLM, all of the five urinary OPI metabolites were inversely associated with free triiodothyronine (FT3) among the male subjects; meanwhile, higher thyroglobulin (Tg) was related to dimethylphosphate (DMP). Moreover, in WQS models, the metabolite mixture induced FT3 down-regulation (β = -0.209 (95% CI: -0.310, -0.114)), and caused an increased Tg concentration (β = 0.120 (95% CI: 0.024, 0.212)), however, any significant association was observed among female participants. Consistently, the weighted index and LASSO coefficient demonstrated dimethylthiophosphate (DMTP) as the strongest metabolite in the FT3 model (mean weight= 3.449e-01 and β =-0.022, respectively), and dimethylphosphate (DMP) represented the highest association in the Tg model (mean weight= 9.873e-01 and β =-0.020, respectively). Further research is required to confirm our results and investigate the clinical impacts of these disruptions.
Topics: Adult; Humans; Male; Female; United States; Insecticides; Nutrition Surveys; Thyroid Hormones; Organophosphates; Organophosphorus Compounds
PubMed: 38428240
DOI: 10.1016/j.ecoenv.2024.116139 -
Toxicology Letters Apr 2012Human paraoxonase 1 (PON1), a 45kDa arylesterase associated with circulating high density lipoproteins (HDL), has been described as an anti-atherogenic element in... (Review)
Review
Human paraoxonase 1 (PON1), a 45kDa arylesterase associated with circulating high density lipoproteins (HDL), has been described as an anti-atherogenic element in cardiovascular disorders. The efficacy of PON1 as a catalytic bioscavenger against OP and CWNA toxicity has been on debate for the last few decades. Hydrolysis of various organophosphates (OPs) and chemical warfare nerve agents (CWNAs) by PON1 has been demonstrated in both in vitro and in vivo experiments. Recently, we established the protective efficacy of human and rabbit serum purified PON1 as well as human recombinant PON1 expressed in Trichoplusia ni larvae against nerve agent toxicity in guinea pigs. Exogenous administration of purified PON1 was effective in protecting against 1.2 X LCt(50) of sarin and soman administered endotracheally with microinstillation technology. However, the short half-life of exogenously administered PON1, probably due to poor association with circulating HDL, warrant alternative approaches for successful utility of PON1 in the treatment of OP/CWNA toxicity. In this mini review, we address the pros and cons of current PON1 prophylaxis and propose potential solutions for successful development of PON1 as an effective catalytic bioscavenger.
Topics: Animals; Aryldialkylphosphatase; Chemical Warfare Agents; Guinea Pigs; Half-Life; Humans; Organophosphates; Rabbits
PubMed: 22301377
DOI: 10.1016/j.toxlet.2012.01.013