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The function of many channels and transporters is enriched by the conformational plasticity of intrinsically disordered regions (IDRs). Copper transporter 1 (Ctr1) is the main entry point for Cu(I) ions in eukaryotes and contains IDRs both at its N-terminal (Nterm) and C-terminal ends. The former delivers copper ions from the extracellular matrix to the selectivity filter in the Ctr1 lumen. However, the molecular mechanism of this process remains elusive due to Nterm's disordered nature. Here, we combine advanced molecular dynamics simulations and circular dichroism experiments to show that Cu(I) ions and a lipidic environment drive the insertion of the Nterm into the Ctr1 selectivity filter, causing its opening. Through a lipid-aided conformational switch of one of the transmembrane helices, the conformational change of the selectivity filter propagates down to the cytosolic gate of Ctr1. Taken together, our results elucidate how conformational variability of IDRs modulates ion transport.
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Cobre , Simulación de Dinámica Molecular , Iones , Transporte IónicoRESUMEN
The surface of nanocrystalline cerium oxide (CeO2) was treated with various chemical agents by a simple postmodification method at 25 °C and atmospheric pressure. Hydrogen peroxide, ammonium persulfate, deionized water, ascorbic acid, and ortho-phosphoric acid were used in order to study and evaluate their effect on surface materials, such as surface area, crystallite size, number of surface hydroxyl groups, particle morphology, and Ce3+/Ce4+ ratio. Paraoxon-methyl (PO) decomposition and inorganic phosphate adsorption were used to evaluate the effect of surface treatment on catalytic and adsorption properties. CeO2 surface was studied by Fourier transform infrared spectroscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and acid-base titration. While the treatment procedure affected the number of surface hydroxyl groups and the amount of bulk surface oxygen vacancies, only negligible changes were observed in the Ce3+/Ce4+ ratio. Interestingly, surface treatment affected the ability to decompose PO, but only a small effect on inorganic phosphate adsorption was observed, indicating the robustness of CeO2 for the latter. A mechanism for possible interaction of the used chemicals with the CeO2 surface was proposed.
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Nanoceria is a promising nanomaterial for the catalytic hydrolysis of a wide variety of substances. In this study, it was experimentally demonstrated for the first time that CeO2 nanostructures show extraordinary reactivity toward sulfonamide drugs (sulfadimethoxine, sulfamerazine, and sulfapyridine) in aqueous solution without any illumination, activation, or pH adjustment. Hydrolytic cleavage of various bonds, including S-N, C-N, and C-S, was proposed as the main reaction mechanism and was indicated by the formation of various reaction products, namely, sulfanilic acid, sulfanilamide, and aniline, which were identified by HPLC-DAD, LC-MS/MS, and NMR spectroscopy. The kinetics and efficiency of the ceria-catalyzed hydrolytic cleavage were dependent on the structure of the sulfonamide molecule and physicochemical properties of Nanoceria prepared by three different precipitation methods. However, in general, all three ceria samples were able to cleave SA drugs tested, proving the robust and unique surface reactivity toward these compounds inherent to cerium dioxide. The demonstrated reactivity of CeO2 to molecules containing sulfonamide or even sulfonyl (and similar) functional groups may be significant for both heterogeneous catalysis and environmentally important degradation reactions.
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Metal-organic frameworks (MOFs) are attracting increasing attention as adsorbents of contaminants of emerging concern that are difficult to remove by conventional processes. This paper examines how functional groups covering the pore walls of phosphinate-based MOFs affect the adsorption of specific pharmaceutical pollutants (diclofenac, cephalexin, and sulfamethoxazole) and their hydrolytic stability. New structures, isoreticular to the phosphinate MOF ICR-7, are presented. The phenyl ring facing the pore wall of the presented MOFs is modified with dimethylamino groups (ICR-8) and ethyl carboxylate groups (ICR-14). These functionalized MOFs were obtained from two newly synthesized phosphinate linkers containing the respective functional groups. The presence of additional functional groups resulted in higher affinity toward the tested pollutants compared to ICR-7 or activated carbon. However, this modification also comes with a reduced adsorption capacity. Importantly, the introduction of the functional groups enhanced the hydrolytic stability of the MOFs.
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The U2AF2 splicing factor is involved in the RNA recognition of the pre-mRNA poly-pyrimidine signaling sequence. This protein contains two RRM domains connected by a flexible linker, which ensure the preferential selection of a poly-uridine sequence over a poly-cytosine one. In this work, all-atom simulations provide insights into the U2AF2 recognition mechanism and on the features underlying its selectivity. Our outcomes show that U2AF2's RNA recognition is driven by cooperative events modulated by RNA-protein and RNA-ion interactions. Stunningly, monovalent ions contribute to mediating the binding of the weakly binding polyC strand, thus contributing to the selection of suboptimal poly-pyrimidine tracts. This finding broadens our understanding of the diverse traits tuning splicing factors' selectivity and adaptability to precisely handle and process diverse pre-mRNA sequences.
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Precursores del ARN , ARN , ARN/química , Precursores del ARN/genética , Precursores del ARN/química , Precursores del ARN/metabolismo , Factores de Empalme de ARN/metabolismo , Secuencia de Bases , Motivo de Reconocimiento de ARN , PirimidinasRESUMEN
RNA recognition motifs (RRMs) play a pivotal role in RNA metabolism and the regulation of gene expression. Owing to their plasticity and fuzziness, targeting RRM/RNA interfaces with small molecules is a daunting challenge for drug discovery campaigns. The U2AF2 splicing factor, which recognizes the polypyrimidine (polyPy) sequence of premature messenger (pre-m)RNA, exhibits a dynamic architecture consisting of two RRMs joined by a disordered linker. An inhibitor, NSC-194308, was shown to enhance the binding of pre-mRNA to U2AF2, selectively triggering cell death in leukemia cell lines containing spliceosome mutations. The NSC-194308 binding mode remains elusive; yet, unraveling its knowledge may offer intriguing insights for effectively targeting U2AF2 and other flexible protein/protein/RNA interfaces with small molecules. To infer plausible NSC-194308 binding poses to U2AF2, here, we applied and benchmarked the performance of static and dynamic docking approaches, elucidating the molecular basis of the NSC-194308-induced pre-mRNA stabilization on U2AF2. We demonstrate that introducing dynamic effects is mandatory to assess the binding mode of the inhibitors when they target plastic and modular architectures, such as those formed by interacting RRMs. The latter are widespread across RNA binding proteins; therefore, this mechanism may be broadly applicable to discover new therapeutics aimed at selectively modulating the RNA function by targeting protein/protein/RNA interfaces.
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Precursores del ARN , Empalme del ARN , Precursores del ARN/genética , Precursores del ARN/metabolismo , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , ARN/metabolismo , Proteínas de Unión al ARN/química , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Abnormal cellular copper levels have been clearly implicated in genetic diseases, cancer, and neurodegeneration. Ctr1, a high-affinity copper transporter, is a homotrimeric integral membrane protein that provides the main route for cellular copper uptake. Together with a sophisticated copper transport system, Ctr1 regulates Cu(I) metabolism in eukaryotes. Despite its pivotal role in normal cell function, the molecular mechanism of copper uptake and transport via Ctr1 remains elusive. In this study, electron paramagnetic resonance (EPR), UV-visible spectroscopy, and all-atom simulations were employed to explore Cu(I) binding to full-length human Ctr1 (hCtr1), thereby elucidating how metal binding at multiple distinct sites affects the hCtr1 conformational dynamics. We demonstrate that each hCtr1 monomer binds up to five Cu(I) ions and that progressive Cu(I) binding triggers a marked structural rearrangement in the hCtr1 C-terminal region. The observed Cu(I)-induced conformational remodeling suggests that the C-terminal region may play a dual role, serving both as a channel gate and as a shuttle mediating the delivery of copper ions from the extracellular hCtr1 selectivity filter to intracellular metallochaperones. Our findings thus contribute to a more complete understanding of the mechanism of hCtr1-mediated Cu(I) uptake and provide a conceptual basis for developing mechanism-based therapeutics for treating pathological conditions linked to de-regulated copper metabolism.
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Proteínas de Transporte de Catión , Proteínas Transportadoras de Cobre , Transportador de Cobre 1 , Cobre , Cobre/química , Cobre/metabolismo , Proteínas Transportadoras de Cobre/química , Proteínas Transportadoras de Cobre/metabolismo , Transportador de Cobre 1/química , Transportador de Cobre 1/metabolismo , Humanos , Iones/química , Iones/metabolismoRESUMEN
The U2AF2 splicing factor, made of two tandem RNA recognition motifs (RRMs) joined by a flexible linker, selects the intronic polypyrimidine sequence of premature mRNA, thus ensuring splicing fidelity. Increasing evidence links mutations of key splicing factors, including U2AF2, to a variety of cancers. Nevertheless, the impact of U2AF2 cancer-associated mutations on polypyrimidine recognition remains unclear. Here, we combined extensive (18 µs-long) all-atom molecular dynamics simulations and dynamical network theory analysis (NWA) of U2AF2, in its wild-type form and in the presence of the six most frequent cancer-associated mutations, bound to a poly-U strand. Our results reveal that the selected mutations affect the pre-mRNA binding at two hot spot regions, irrespectively of where these mutants are placed on the distinct U2AF2 domains. Complementarily, NWA traced the existence of cross-communication pathways, connecting each mutation site to these recognition hot spots, whose strength is altered by the mutations. Our outcomes suggest the existence of a structural/dynamical interplay of the two U2AF2's RRMs underlying the recognition of the polypyrimidine tract and reveal that the cancer-associated mutations affect the polypyrimidine selection by altering the RRMs' cooperativity. This mechanism may be shared by other RNA binding proteins hallmarked, like U2AF2, by multidomain architecture and high plasticity.
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Neoplasias , Precursores del ARN , Humanos , Precursores del ARN/genética , Precursores del ARN/metabolismo , Empalme del ARN , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Neoplasias/genética , Mutación , Factor de Empalme U2AF/genética , Factor de Empalme U2AF/metabolismoRESUMEN
The secondary active Na-K-Cl cotransporter 1 (NKCC1) promotes electroneutral uptake of two chloride ions, one sodium ion and one potassium ion. NKCC1 regulates Cl- homeostasis, thus being implicated in transepithelial water transport and in neuronal excitability. Aberrant NKCC1 transport is linked to a variety of human diseases. The loop diuretic drugs bumetanide, furosemide, azosemide and ethacrynic acid target NKCC1, but are characterized by poor selectivity leading to severe side effects. Despite its therapeutic importance, the molecular details of the NKCC1 inhibition mechanism remain unclear. Using all-atom simulations, we predict a putative binding mode of these drugs to the zebrafish (z) and human (h) NKCC1 orthologs. Although differing in their specific interactions with NKCC1 and/or monovalent ions, all drugs can fit within the same cavity and engage in hydrophobic interactions with M304/M382 in z/hNKCC1, a proposed ion gating residue demonstrated to be key for bumetanide binding. Consistent with experimental evidence, all drugs take advantage of the K+/Na+ ions, which plastically respond to their binding. This study not only provides atomic-level insights useful for drug discovery campaigns of more selective/potent NKCC1 inhibitors aimed to tackle diseases related to deregulated Cl- homeostasis, but it also supplies a paradigmatic example of the key importance of dynamical effects when drug binding is mediated by monovalent ions.
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Bumetanida , Pez Cebra , Animales , Humanos , Pez Cebra/metabolismo , Bumetanida/farmacología , Miembro 2 de la Familia de Transportadores de Soluto 12 , Potasio/metabolismo , Sodio/metabolismo , Cloruros/metabolismo , Cotransportadores de K ClRESUMEN
The secondary-active Na-K-Cl cotransporter 1 (NKCC1), member of the cation-chloride cotransporter (CCC) family, ensures the electroneutral movement of Cl-, Na+, and K+ ions across cellular membranes. NKCC1 regulates Cl- homeostasis and cell volume, handling a pivotal role in transepithelial water transport and neuronal excitability. Aberrant NKCC1 transport is hence implicated in a variety of human diseases (hypertension, renal disorders, neuropathies, and cancer). Building on the newly resolved NKCC1 cryo-EM structure, all-atom enhanced sampling simulations unprecedentedly unlock the mechanism of NKCC1-mediated ion transport, assessing the order and the molecular basis of its interdependent ion translocation. Our outcomes strikingly advance the understanding of the physiological mechanism of CCCs and disclose a key role of CCC-conserved asparagine residues, whose side-chain promiscuity ensures the transport of both negatively and positively charged ions along the same translocation route. This study sets a conceptual basis to devise NKCC-selective inhibitors to treat diseases linked to Cl- dishomeostasis.
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Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Simportadores , Transporte Biológico , Humanos , Transporte Iónico , Sodio/metabolismo , Cotransportadores de K ClRESUMEN
Mycobacterium tuberculosis features a unique cell wall that protects the bacterium from the external environment. Disruption of the cell wall assembly is a promising direction for novel anti-tuberculotic drugs. A key component of the cell wall is galactan, a polysaccharide chain composed of galactofuranose (Galf) units connected by alternating ß-(1-5) and ß-(1-6) linkages. The majority of the galactan chain is biosynthesized by a bifunctional enzyme-galactofuranosyl transferaseâ 2 (GlfT2). GlfT2 catalyzes two reactions: the formation of ß-(1-5) and ß-(1-6) linkages. It was suggested that the enzyme acts through a processive mechanism until it adds 30-35 Galf units in a single active site. We applied a QM/MM string method coupled with ab initio molecular dynamics simulations to study the two reactions catalyzed by GlfT2. We showed that both reactions proceed very similarly and feature similar transition-state structures. We also present novel information about the ring puckering behavior of the five-membered furanose ring during the glycosyltransferase reaction and a calculated transition-state structure with galactose in a furanose form that may be used as a guide for the rational design of very specific and extremely potent inhibitors, that is, transition-state analogues, for GlfT2. Due to the absence of a furanose form of galactose in humans, transition-state-analogous inhibitors represent an attractive scaffold for the development of novel antibacterial drugs.
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Proteínas Bacterianas/metabolismo , Galactosiltransferasas/metabolismo , Simulación de Dinámica Molecular , Mycobacterium tuberculosis/enzimología , Teoría Cuántica , Proteínas Bacterianas/química , Sitios de Unión , Dominio Catalítico , Galactosa/química , Galactosa/metabolismo , Galactosiltransferasas/química , Especificidad por Sustrato , TermodinámicaRESUMEN
The enzyme UDP-N-acetylglucosamine: α-d-mannoside ß-1-6 N-acetylglucosaminyltransferase V (GnT-V) catalyzes the transfer of GlcNAc from the UDP-GlcNAc donor to the α-1-6-linked mannose of the trimannosyl core structure of glycoproteins to produce the ß-1-6-linked branching of N-linked oligosaccharides. ß-1-6-GlcNAc-branched N-glycans are associated with cancer growth and metastasis. Therefore, the inhibition of GnT-V represents a key target for anti-cancer drug development. However, the development of potent and specific inhibitors of GnT-V is hampered by the lack of information on the three-dimensional structure of the enzyme and on the binding characteristics of its substrates. Here we present the first 3D structure of GnT-V as a result of homology modeling. Various alignment methods, docking the donor and acceptor substrates, and molecular dynamics simulation were used to construct seven homology models of GnT-V and characterize the binding of its substrates. The best homology model is consistent with available experimental data. The three-dimensional model, the structure of the enzyme catalytic site and binding information obtained for the donor and acceptor can be useful in studies of the catalytic mechanism and design of inhibitors of GnT-V.
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Glicosiltransferasas/química , Conformación Molecular , N-Acetilglucosaminiltransferasas/química , Polisacáridos/química , Humanos , Manosa/química , Modelos Moleculares , Simulación de Dinámica Molecular , Polisacáridos/genética , Especificidad por SustratoRESUMEN
Metal oxides have very important applications in many areas of chemistry, physics and materials science; their properties are dependent on the method of preparation, the morphology and texture. Nanostructured metal oxides can exhibit unique characteristics unlike those of the bulk form depending on their morphology, with a high density of edges, corners and defect surfaces. In recent years, methods have been developed for the preparation of metal oxide powders with tunable control of the primary particle size as well as of a secondary particle size: the size of agglomerates of crystallites. One of the many ways to take advantage of unique properties of nanostructured oxide materials is stoichiometric degradation of chemical warfare agents (CWAs) and volatile organic compounds (VOC) pollutants on their surfaces.
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Sustancias para la Guerra Química/química , Contaminantes Ambientales/química , Restauración y Remediación Ambiental , Nanopartículas del Metal/química , Óxidos/químicaRESUMEN
The pillar of faithful premature-messenger (pre-mRNA) splicing is the precise recognition of key intronic sequences by specific splicing factors. The heptameric splicing factor 3b (SF3b) recognizes the branch point sequence (BPS), a key part of the 3' splice site. SF3b contains SF3B1, a protein holding recurrent cancer-associated mutations. Among these, K700E, the most-frequent SF3B1 mutation, triggers aberrant splicing, being primarily implicated in hematologic malignancies. Yet, K700E and the BPS recognition site are 60 Å apart, suggesting the existence of an allosteric cross-talk between the two distal spots. Here, we couple molecular dynamics simulations and dynamical network theory analysis to unlock the molecular terms underpinning the impact of SF3b splicing factor mutations on pre-mRNA selection. We establish that by weakening and remodeling interactions of pre-mRNA with SF3b, K700E scrambles RNA-mediated allosteric cross-talk between the BPS and the mutation site. We propose that the altered allostery contributes to cancer-associated missplicing by mutated SF3B1. This finding broadens our comprehension of the elaborate mechanisms underlying pre-mRNA metabolism in eukaryotes.
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Neoplasias , Precursores del ARN , Humanos , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , ARN Mensajero , Precursores del ARN/genética , Precursores del ARN/metabolismo , ARN , Mutación , Neoplasias/genética , Factores de TranscripciónRESUMEN
Two types of CeO2 nanoparticles (CeNPs) prepared by low-temperature (<100 °C) precipitation methods in water were successfully immobilized in a matrix of electrospun PA6 nanofibers. The colloidal solutions of CeNPs in AcOH were directly mixed with the polymer solution before the needle electrospinning process, thereby achieving their good dispersion in the nanofibers. CeNPs embedded in the structure and on the surface of nanofibers exposing their reactive surfaces showed robust dephosphorylation catalytic activity, as demonstrated by monitoring the hydrolytic cleavage of three phosphodiester molecules (p-NP-TMP, p-NPPC, BNPP) in water by the HPLC method. This procedure allowed us to study the kinetics and mechanism of the hydrolytic cleavage and the ability of immobilized CeNPs to cleave different types of P-O bonds. One of the main hydrolysis products, p-nitrophenol, was effectively adsorbed on PA6 nanofibers, which may allow the selective separation of the degradation products after hydrolysis.
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Copper is a trace element vital to many cellular functions. Yet its abnormal levels are toxic to cells, provoking a variety of severe diseases. The high affinity copper transporter 1 (CTR1), being the main in-cell copper [Cu(I)] entry route, tightly regulates its cellular uptake via a still elusive mechanism. Here, all-atoms simulations unlock the molecular terms of Cu(I) transport in eukaryotes disclosing that the two methionine (Met) triads, forming the selectivity filter, play an unprecedented dual role both enabling selective Cu(I) transport and regulating its uptake rate thanks to an intimate coupling between the conformational plasticity of their bulky side chains and the number of bound Cu(I) ions. Namely, the Met residues act as a gate reducing the Cu(I) import rate when two ions simultaneously bind to CTR1. This may represent an elegant autoregulatory mechanism through which CTR1 protects the cells from excessively high, and hence toxic, in-cell Cu(I) levels. Overall, our outcomes resolve fundamental questions in CTR1 biology and open new windows of opportunity to tackle diseases associated with an imbalanced copper uptake.
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INTRODUCTION: RNA splicing is a pivotal step of eukaryotic gene expression during which the introns are excised from the precursor (pre-)RNA and the exons are joined together to form mature RNA products (i.e a protein-coding mRNA or long non-coding (lnc)RNAs). The spliceosome, a complex ribonucleoprotein machine, performs pre-RNA splicing with extreme precision. Deregulated splicing is linked to cancer, genetic, and neurodegenerative diseases. Hence, the discovery of small-molecules targeting core spliceosome components represents an appealing therapeutic opportunity. AREA COVERED: Several atomic-level structures of the spliceosome and distinct splicing-modulators bound to its protein/RNA components have been solved. Here, we review recent advances in the discovery of small-molecule splicing-modulators, discuss opportunities and challenges for their therapeutic applicability, and showcase how structural data and/or all-atom simulations can illuminate key facets of their mechanism, thus contributing to future drug-discovery campaigns. EXPERT OPINION: This review highlights the potential of modulating pre-RNA splicing with small-molecules, and anticipates how the synergy of computer and wet-lab experiments will enrich our understanding of splicing regulation/deregulation mechanisms. This information will aid future structure-based drug-discovery efforts aimed to expand the currently limited portfolio of selective splicing-modulators.
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Precursores del ARN , Empalmosomas , Humanos , Intrones , Precursores del ARN/química , Precursores del ARN/genética , Precursores del ARN/metabolismo , Empalme del ARN , Empalmosomas/química , Empalmosomas/genética , Empalmosomas/metabolismoRESUMEN
Nanoscale cerium-bismuth oxides/oxynitrates were prepared by a scalable low-temperature method at ambient pressure using water as the sole solvent. Solid solutions were formed up to a 1:1 Ce/Bi molar ratio, while at higher doping levels, bismuth oxynitrate photocatalysts with a pronounced layered structure were formed. Bismuth caused significant changes in the structure and surface properties of nanoceria, such as the formation of defects, oxygen-containing surface groups, and Lewis and Brønsted acid sites. The prepared bifunctional adsorbents/photocatalysts were efficient in the removal of toxic organophosphate (methyl paraoxon) from water by reactive adsorption followed by photocatalytic decomposition of the parent compound and its degradation product (p-nitrophenol). Bi-doped ceria also effectively adsorbed and photodegraded the endocrine disruptors bisphenols A and S and outperformed pure ceria and the P25 photocatalyst in terms of efficiency, durability, and long-term stability. The very low toxicity of Bi-nanoceria to mammalian cells, aquatic organisms, and bacteria has been demonstrated by comprehensive in vivo/in vitro testing, which, in addition to its simple "green" synthesis, high activity, and durability, makes Bi-doped ceria promising for safe use in abatement of toxic chemicals.
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Metallodrugs are extensively used to treat and diagnose distinct disease types. The unique physical-chemical properties of metal ions offer tantalizing opportunities to tailor effective scaffolds for selectively targeting specific biomolecules. Modern experimental techniques have collected a large body of structural data concerning the interactions of metallodrugs with their biomolecular targets, although being unable to exhaustively assess the molecular basis of their mechanism of action. In this scenario, the complementary use of accurate computational methods allows uncovering the minutiae of metallodrugs/targets interactions and their underlying mechanism of action at an atomic-level of detail. This knowledge is increasingly perceived as an invaluable requirement to rationally devise novel and selective metallodrugs. Building on literature studies, selected largely from the last 2 years, this compendium encompasses a cross-section of the current role, advances, and challenges met by computer simulations to decipher the mechanistic intricacies of prototypical metallodrugs.
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Complejos de Coordinación/farmacología , Metales/química , Antineoplásicos/química , Antineoplásicos/farmacología , Química Computacional , Complejos de Coordinación/química , Humanos , Simulación de Dinámica Molecular , Teoría CuánticaRESUMEN
Regenerated bead cellulose is a promising material with excellent mechanical and rheological properties, ideally suited for advanced environmental applications. By introducing the amidoxime functional group into the glucose unit at the C-6 position, highly effective reactive sorbent was prepared and used to destroy priority hazardous substances such as organophosphate pesticides or nerve-paralytic chemical warfare agents (CWAs). Quantum mechanical (QM) calculations were performed to study the interactions of organophosphates with amidoxime functional groups at the molecular level. It was found that the energetic reaction barrier of the rate-limiting step is markedly reduced (from 31.40 to 11.37 kcal mol-1) in the case of the amidoxime-catalysed degradation of parathion methyl, which resulted in a dramatic increase in the degradation rate; this was fully confirmed by experiments, in which the pesticide degradation proceeded at the time scale of several hours (t 1/2 = 20-30 hours at pH 7.22).