Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 29
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Phys Chem Lett ; 11(4): 1189-1193, 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-31986051

RESUMO

Cytochromes P450 enzymes (CYP450s) promote the oxidative metabolism of a variety of substrates via the electrons supplied by the cytochrome P450 reductase (CPR) and upon formation of a CPR/CYP450 adduct. In spite of the pivotal regulatory importance of this process, the impact of CPR binding on the functional properties of its partner CYP450 remains elusive. By performing multiple microsecond-long all-atom molecular dynamics simulations of a 520 000-atom model of a CPR/CYP450 adduct embedded in a membrane mimic, we disclose the molecular terms for their interactions, considering the aromatase (HA) enzyme as a proxy of the CYP450 family. Our study strikingly unveils that CPR binding alters HA's functional motions, bolstering a change in the shape and type of the channels traveled by substrates/products during their access/egress to/from the enzyme's active site. Our outcomes unprecedentedly contribute to extricate the many entangled facets of the CYP450 metabolon, redrafting its intricate panorama from an atomic-level perspective.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Aromatase/química , Aromatase/metabolismo , Sistema Enzimático do Citocromo P-450/química , Transporte de Elétrons , Humanos , Simulação de Dinâmica Molecular , NADPH-Ferri-Hemoproteína Redutase/química , Ligação Proteica , Especificidade por Substrato
2.
Antioxidants (Basel) ; 8(10)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658666

RESUMO

The DNA-binding of the natural benzophenanthridine alkaloid chelerythrine (CHE) has been assessed by combining molecular modeling and optical absorption spectroscopy. Specifically, both double-helical (B-DNA) and G-quadruplex sequences-representative of different topologies and possessing biological relevance, such as telomeric or regulatory sequences-have been considered. An original multiscale protocol, making use of molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, allowed us to compare the theoretical and experimental circular dichroism spectra of the different DNA topologies, readily providing atomic-level details of the CHE-DNA binding modes. The binding selectivity towards G-quadruplexes is confirmed by both experimental and theoretical determination of the binding free energies. Overall, our mixed computational and experimental approach is able to shed light on the interaction of small molecules with different DNA conformations. In particular, CHE may be seen as the building block of promising drug candidates specifically targeting G-quadruplexes for both antitumoral and antiviral purposes.

3.
Front Chem ; 7: 602, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31552220

RESUMO

The most frequently diagnosed cancers in women are the estrogen receptor (ER)-positive breast cancer subtypes, which are characterized by estrogen dependency for their growth. The mainstay of clinical treatment for this tumor relies on the modulation of ERα action or on the suppression of estrogen biosynthesis via the administration of Selective ERα Modulators/Down-regulators (SERMs/SERDs) or aromatase inhibitors, respectively. Nevertheless, de novo and acquired resistance to these therapies frequently occurs and represents a major clinical concern for patient survival. Recently, somatic mutations affecting the hormone-binding domain of ERα (i.e., Y537S, Y537N, D538G) have been associated with endocrine resistance, disease relapse and increased mortality rates. Hence, devising novel therapies against these ERα isoforms represents a daunting challenge. Here, we identified five molecules active on recurrent Y537S ERα polymorphism by employing in silico virtual screening on commercial databases of molecules, complemented by ER-transactivation and MTT assays in MCF7 and MDA-MB-231 breast cancer cells expressing wild type or mutated ERα. Among them, one molecule selectively targets Y537S ERα without inducing any cytotoxicity in breast cell lines. Multi-microseconds (4.5 µs) of biased and unbiased molecular dynamics provided an atomic-level picture of the structural, thermodynamics (i.e., binding free energies) and the kinetic (i.e., dissociation free energy barriers) of these active ligands as compared to clinically used SERM/SERDs upon binding to wild type and distinct ERα variants (Y537S, Y537N, D538G). This study contributes to a dissection of the key molecular traits needed by drug-candidates to hamper the agonist (active)-like conformation of ERα, normally selected by those polymorphic variants. This information can be useful to discover mutant specific drug-candidates, enabling to move a step forward toward tailored approaches for breast cancer treatment.

4.
J Chem Inf Model ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31539251

RESUMO

Splicing modulators (SMs) pladienolides, herboxidienes, and spliceostatins exert their antitumor activity by altering the ability of SF3B1 and PHF5A proteins, components of SF3b splicing factor, to recognize distinct intron branching point sequences, thus finely calibrating constitutive/alternative/aberrant splicing of pre-mRNA. Here, by exploiting structural information obtained from cryo-EM data, and by performing multiple µs-long all-atom simulations of SF3b in apo form and in complex with selected SMs, we disclose how these latter seep into the narrow slit at the SF3B1/PHF5A protein interface. This locks the intrinsic open/closed conformational transitions of SFB1's solenoidal structure into the open state. As a result, SMs prevent the formation of a closed/intron-loaded conformation of the SF3B1 protein by decreasing the internal SF3B1 cross-correlation and reducing SF3B1's functional plasticity. We further compellingly support the proposition that SMs' action exceeds a purely competitive inhibition. Indeed, our simulations also demonstrate that the introduction of recurrent drug resistance/sensitizing mutations in SF3B1 or PHF5A, besides affecting the binding affinity of SMs, likewise influence the functional dynamics of SF3B1. This knowledge clarifies the molecular terms of SF3b modulation by small-molecules, fostering the rational-based discovery of drugs tackling distinct cancer types resulting from dysregulated splicing. This work also supports the coming of age usage of cryo-EM structural data in forthcoming drug-discovery studies.

5.
Expert Opin Drug Discov ; 14(10): 1065-1076, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31339372

RESUMO

Introduction: The vast majority of breast cancers (BC) are estrogen receptor positive (ER+). The most effective treatments to fight this BC type rely on estrogen deprivation therapy, by inhibiting the aromatase enzyme, which performs estrogen biosynthesis, or on blocking the estrogens signaling path via modulating/degrading the estrogen's specific nuclear receptor (estrogen receptor-α, ERα). While being effective at early disease stage, patients treated with aromatase inhibitors (AIs) may acquire resistance and often relapse after prolonged therapies. Areas covered: In this compendium, after an overview of the historical development of the AIs currently in clinical use, and of the computational tools which were used to identify them, the authors focus on current advances in obtaining innovative inhibitors via molecular simulations. These inhibitors may help prevent or delay relapse to AIs. Expert opinion: BC remains the most diagnosed and the leading cause of death in women. In spite of the success of the adjuvant endocrine therapy, which has enormously prolonged woman's survival rate, the increasing emergence of the resistance phenomena calls for the development of novel approaches and drugs to fight it. The discovery of the last generation of AIs dates back to two decades ago, underlying a paucity of research efforts.

6.
J Chem Inf Model ; 59(6): 2930-2940, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31033287

RESUMO

Phosphorylation by kinases enzymes is a widespread regulatory mechanism able of rapidly altering the function of target proteins. Among these are cytochrome P450s (CYP450), a superfamily of enzymes performing the oxidation of endogenous and exogenous substrates thanks to the electron supply of a redox partner. In spite of its pivotal role, the molecular mechanism by which phosphorylation modulates CYP450s metabolism remains elusive. Here by performing microsecond-long all-atom molecular dynamics simulations, we disclose how phosphorylation regulates estrogen biosynthesis, catalyzed by the Human Aromatase (HA) enzyme. Namely, we unprecedentedly propose that HA phosphorylation at Y361 markedly stabilizes its adduct with the flavin mononucleotide domain of CYP450s reductase (CPR), the redox partner of microsomal CYP450s, and a variety of other proteins. With CPR present at physiological conditions in a limiting ratio with respect to its multiple oxidative partners, the enhanced stability of the CPR/HA adduct may favor HA in the competition with the other proteins requiring CPR's electron supply, ultimately facilitating the electron transfer and estrogen biosynthesis. As a result, our work elucidates at atomic-level the post-translational regulation of CYP450s catalysis. Given the potential for rational clinical management of diseases associated with steroid metabolism disorders, unraveling this mechanism is of utmost importance, and raises the intriguing perspective of exploiting this knowledge to devise novel therapies.

7.
Future Med Chem ; 11(7): 771-791, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30938544

RESUMO

Metallo-enzymes are a large class of biomolecules promoting specialized chemical reactions. Quantum-classical quantum mechanics/molecular mechanics molecular dynamics, describing the metal site at quantum mechanics level, while accounting for the rest of system at molecular mechanics level, has an accessible time-scale limited by its computational cost. Hence, it must be integrated with classical molecular dynamics and enhanced sampling simulations to disentangle the functions of metallo-enzymes. In this review, we provide an overview of these computational methods and their capabilities. In particular, we will focus on some systems such as CYP19A1 a Fe-dependent enzyme involved in estrogen biosynthesis, and on Mg2+-dependent DNA/RNA processing enzymes/ribozymes and the spliceosome, a protein-directed ribozyme. This information may guide the discovery of drug-like molecules and genetic manipulation tools.

8.
Eur J Med Chem ; 168: 253-262, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30822713

RESUMO

Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we identified five leads inhibiting the enzyme via a non-active site-directed mechanism. This study provides new compelling evidences for the existence of an allosteric regulation of aromatase and for the possibility of exploiting it to modulate estrogens biosynthesis. Such modulation can aptly reduce side effects caused by the complete estrogen deprivation therapy, and, possibly, delay/avoid the onset of resistance.


Assuntos
Antineoplásicos/farmacologia , Aromatase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Desenho de Drogas , Inibidores Enzimáticos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-Atividade
9.
Mar Drugs ; 17(3)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857142

RESUMO

Due to the limited number of available antibiotics, antimicrobial peptides (AMPs) are considered antimicrobial candidates to fight difficult-to-treat infections such as those associated with biofilms. Marine environments are precious sources of AMPs, as shown by the recent discovery of antibiofilm properties of Holothuroidin 2 (H2), an AMP produced by the Mediterranean sea cucumber Holothuria tubulosa. In this study, we considered the properties of a new H2 derivative, named H2d, and we tested it against seven strains of the dangerous foodborne pathogen Listeria monocytogenes. This peptide was more active than H2 in inhibiting the growth of planktonic L. monocytogenes and was able to interfere with biofilm formation at sub-minimum inhibitory concentrations (MICs). Atomic-level molecular dynamics (MD) simulations revealed insights related to the enhanced inhibitory activity of H2d, showing that the peptide is characterized by a more defined tertiary structure with respect to its ancestor. This allows the peptide to better exhibit an amphipathic character, which is an essential requirement for the interaction with cell membranes, similarly to other AMPs. Altogether, these results support the potential use of our synthetic peptide, H2d, as a template for the development of novel AMP-based drugs able to fight foodborne that are resistant to conventional antibiotics.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Holothuria , Listeria monocytogenes/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Biofilmes/efeitos dos fármacos , Desenho de Drogas , Farmacorresistência Bacteriana , Doenças Transmitidas por Alimentos/tratamento farmacológico , Doenças Transmitidas por Alimentos/microbiologia , Doenças Transmitidas por Alimentos/patologia , Listeria monocytogenes/isolamento & purificação , Listeria monocytogenes/fisiologia , Listeriose/tratamento farmacológico , Listeriose/microbiologia , Listeriose/patologia , Mar Mediterrâneo , Testes de Sensibilidade Microbiana , Simulação de Dinâmica Molecular , Estrutura Terciária de Proteína
10.
J Chem Inf Model ; 59(1): 351-359, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30586302

RESUMO

Multiple mechanisms of cell death exist (apoptosis, necroptosis, pyroptosis) and the subtle balance of several distinct proteins and inhibitors tightly regulates the cell fate toward one or the other pathway. Here, by combining coimmunoprecipitation, enzyme assays, and molecular simulations, we ascribe a new role, within this entangled regulatory network, to the interleukin-1 receptor antagonist (IL-1Ra). Our study enlightens that IL-1Ra, which usually inhibits the inflammatory effects of IL-1α/ß by binding to IL-1 receptor, under advanced pathological states prevents apoptosis and/or necroptosis by noncompetitively inhibiting the activity of caspase-8 and -9. Consensus docking, followed by cumulative 10 µs of molecular dynamics simulations unprecedentedly reveal that IL-1Ra binds both caspases at their dimeric interface, preventing, in this manner, the formation of their catalytically/signaling active form. The resulting IL-1Ra/caspase-8(9) adducts are stabilized by hydrophobic and by few key hydrogen bonding interactions, formed by residues fully conserved across distinct caspases (-3, -6, -7, -8, and -9), and closely resemble the binding mode of the caspases inhibitors XIAP (X-linked inhibitor of apoptosis) and c-FLIP (cellular FLICE-like inhibitory protein). Tight regulation of the different forms of cell death has a major impact on distinct human illnesses (i.e., cancer, neurodegeneration, ischemic injury, atherosclerosis, viral/bacterial infections, and immune reaction). Hence, our study, pinpointing IL-1Ra as new actor of the intricate cell death regulatory network and gaining an atomic-scale understanding of its mechanism may open new avenues toward innovative therapeutic strategies to tackle major human diseases.


Assuntos
Morte Celular , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Simulação de Dinâmica Molecular , Caspase 8/metabolismo , Caspase 9/metabolismo , Biologia Computacional , Ativação Enzimática , Proteína Antagonista do Receptor de Interleucina 1/química , Conformação Proteica , Receptores de Interleucina-1/metabolismo , Termodinâmica
11.
Mar Drugs ; 16(10)2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279359

RESUMO

With the aim to obtain new antimicrobials against important pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, we focused on antimicrobial peptides (AMPs) from Echinoderms. An example of such peptides is Paracentrin 1 (SP1), a chemically synthesised peptide fragment of a sea urchin thymosin. In the present paper, we report on the biological activity of a Paracentrin 1 derivative obtained by recombination. The recombinant paracentrin RP1, in comparison to the synthetic SP1, is 22 amino acids longer and it was considerably more active against the planktonic forms of S. aureus ATCC 25923 and P. aeruginosa ATCC 15442 at concentrations of 50 µg/mL. Moreover, it was able to inhibit biofilm formation of staphylococcal and P. aeruginosa strains at concentrations equal to 5.0 and 10.7 µg/mL, respectively. Molecular dynamics (MD) simulations allowed to rationalise the results of the experimental investigations, providing atomistic insights on the binding of RP1 toward models of mammalian and bacterial cell membranes. Overall, the results obtained point out that RP1 shows a remarkable preference for bacterial membranes, in excellent agreement with the antibacterial activity, highlighting the promising potential of using the tested peptide as a template for the development of novel antimicrobial agents.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Paracentrotus/metabolismo , Peptídeos/metabolismo , Proteínas Recombinantes/metabolismo , Ouriços-do-Mar/metabolismo , Timosina/metabolismo , Animais , Testes de Sensibilidade Microbiana/métodos , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
12.
Proc Natl Acad Sci U S A ; 115(26): 6584-6589, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29891649

RESUMO

The spliceosome (SPL) is a majestic macromolecular machinery composed of five small nuclear RNAs and hundreds of proteins. SPL removes noncoding introns from precursor messenger RNAs (pre-mRNAs) and ligates coding exons, giving rise to functional mRNAs. Building on the first SPL structure solved at near-atomic-level resolution, here we elucidate the functional dynamics of the intron lariat spliceosome (ILS) complex through multi-microsecond-long molecular-dynamics simulations of ∼1,000,000 atoms models. The ILS essential dynamics unveils (i) the leading role of the Spp42 protein, which heads the gene maturation by tuning the motions of distinct SPL components, and (ii) the critical participation of the Cwf19 protein in displacing the intron lariat/U2 branch helix. These findings provide unprecedented details on the SPL functional dynamics, thus contributing to move a step forward toward a thorough understanding of eukaryotic pre-mRNA splicing.


Assuntos
Simulação por Computador , Íntrons/genética , Modelos Genéticos , Conformação de Ácido Nucleico , Precursores de RNA/metabolismo , Processamento de RNA/fisiologia , Proteínas Repressoras/fisiologia , Ribonucleoproteína Nuclear Pequena U5/fisiologia , Proteínas de Schizosaccharomyces pombe/fisiologia , Spliceossomos/fisiologia , Magnésio/fisiologia , Modelos Moleculares , Simulação de Dinâmica Molecular , Movimento (Física) , Análise de Componente Principal , Conformação Proteica , Precursores de RNA/genética , RNA Fúngico/genética , RNA Fúngico/metabolismo , RNA Nuclear Pequeno/genética , RNA Nuclear Pequeno/metabolismo , Proteínas Repressoras/química , Ribonucleoproteína Nuclear Pequena U5/química , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/química , Eletricidade Estática
13.
Chemistry ; 24(42): 10840-10849, 2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-29770981

RESUMO

Cytochrome P450 (CYP450) enzymes are involved in the metabolism of exogenous compounds and in the synthesis of signaling molecules. Among the latter, human aromatase (HA) promotes estrogen biosynthesis, which is a key pharmacological target against breast cancers. After decades of debate, interest in gaining a comprehensive picture of HA catalysis has been renewed by the recent discovery that compound I (Cpd I) is the reactive species of the peculiar aromatization step. Herein, for the first time, a complete atomic-level picture of all controversial steps of estrogen biosynthesis is presented. By performing cumulative quantum-classical molecular dynamics and metadynamics simulations of about 180 ps, it is revealed that the most likely enzymatic path relies on three factors: 1) androstenedione enolization and compound 0 (Cpd 0) formation through a proton network mediated by Asp309; 2) subsequent formation of Cpd I, upon rearrangement of the Asp309 side chain and the establishment of a proton network involving Asp309 and Thr310; and 3) after two hydroxylation reactions, 19,19-gem-diol is converted into estrone by Cpd I, through an uncommon dehydrogenase-like dual hydrogen abstraction mechanism. As a result, HA performs estrogen biosynthesis by merging hydroxylase with dehydrogenase activity, which suggests that the need to perform complex chemical transformations led nature to engineer HA, and possibly other steroidogenic CYP450s, by expanding its range of functions to achieve an optimal catalytic efficiency.


Assuntos
Androstenodiona/metabolismo , Aromatase/metabolismo , Sistema Enzimático do Citocromo P-450/química , Estrogênios/química , Hidrogênio/química , Androstenodiona/química , Aromatase/química , Catálise , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Hidroxilação , Simulação de Dinâmica Molecular , Oxirredução , Oxirredutases , Prótons
14.
Sci Rep ; 8(1): 649, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330437

RESUMO

Somatic mutations of the Estrogen Receptor α (ERα) occur with an up to 40% incidence in ER sensitive breast cancer (BC) patients undergoing prolonged endocrine treatments. These polymorphisms are implicated in acquired resistance, disease relapse, and increased mortality rates, hence representing a current major clinical challenge. Here, multi-microseconds (12.5 µs) molecular dynamics simulations revealed that recurrent ERα polymorphisms (i. e. L536Q, Y537S, Y537N, D538G) (mERα) are constitutively active in their apo form and that they prompt the selection of an agonist (active)-like conformation even upon antagonists binding. Interestingly, our simulations rationalize, for the first time, the efficacy profile of (pre)clinically used Selective Estrogen Receptor Modulators/Downregulators (SERMs/SERDs) against these variants, enlightening, at atomistic level of detail, the key common structural traits needed by drugs able to effectively fight refractory BC types. This knowledge represents a key advancement for mechanism-based therapeutics targeting resistant ERα isoforms, potentially allowing the community to move a step closer to 'precision medicine' calibrated on patients' genetic profiles and disease progression.


Assuntos
Neoplasias da Mama/metabolismo , Antagonistas do Receptor de Estrogênio/química , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Antagonistas do Receptor de Estrogênio/farmacologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Feminino , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Estrutura Secundária de Proteína
16.
Expert Opin Drug Discov ; 12(8): 813-825, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28604114

RESUMO

INTRODUCTION: Metallo-drugs have attracted enormous interest for cancer treatment. The achievements of this drug-type are summarized by the success story of cisplatin. That being said, there have been many drawbacks with its clinical use, which prompted decades worth of research efforts to move towards safer and more effective agents, either containing platinum or different metals. Areas covered: In this review, the authors provide an atomistic picture of the molecular mechanisms involving selected metallo-drugs from structural and molecular simulation studies. They also provide an omics perspective, pointing out many unsettled aspects of the most relevant families of metallo-drugs at an epigenetic level. Expert opinion: Molecular simulations are able to provide detailed information at atomistic and temporal (ps) resolutions that are rarely accessible to experiments. The increasing accuracy of computational methods and the growing performance of computational platforms, allow us to mirror wet lab experiments in silico. Consequently, the molecular mechanisms of drugs action/failure can be directly viewed on a computer screen, like a 'computational microscope', allowing us to harness this knowledge for the design of the next-generation of metallo-drugs.


Assuntos
Antineoplásicos/farmacologia , Metais/química , Neoplasias/tratamento farmacológico , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Cisplatino/administração & dosagem , Cisplatino/farmacologia , Simulação por Computador , Projeto Auxiliado por Computador , Desenho de Drogas , Epigênese Genética , Humanos , Neoplasias/patologia
17.
World J Microbiol Biotechnol ; 32(8): 124, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27339305

RESUMO

Conventional antibiotics might fail in the treatment of biofilm-associated infections causing infection recurrence and chronicity. The search for antimicrobial peptides has been performed with the aim to discover novel anti-infective agents active on pathogens in both planktonic and biofilm associated forms. The fragment 9-19 of human thymosin ß4 was studied through 1 µs MD simulation. Two main conformations of the peptide were detected, both constituted by a central hydrophobic core and by the presence of peripheral charged residues suggesting a possible mechanism of interaction with two models of biological membranes, related to eukaryotic or bacterial membrane respectively. In addition, the peptide was chemically synthesized and its antimicrobial activity was tested in vitro against planktonic and biofilm form of a group of reference strains of Staphylococcus spp. and one P. aeruginosa strain. The human thymosin ß4 fragment EIEKFDKSKLK showed antibacterial activity against staphylococcal strains and Pseudomonas aeruginosa ATCC 15442 at concentrations from 12.5 to 6.2 mg/ml and inhibited biofilm formation at sub-inhibitory concentrations (3.1-0.75 mg/ml). The activity of the fragment in inhibiting biofilm formation, could be due to the conformations highlighted by the MD simulations, suggesting its interaction with the bacterial membrane. Human thymosin ß4 fragment can be considered a promising lead compound to develop novel synthetic or recombinant derivatives with improved pharmaceutical potential.


Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Peptídeos/síntese química , Peptídeos/farmacologia , Timosina/genética , Sequência de Aminoácidos , Anti-Infecciosos/química , Biofilmes , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Simulação de Dinâmica Molecular , Peptídeos/química , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Timosina/química
18.
Curr Pharm Des ; 22(26): 3996-4010, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27197799

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia that seriously affects daily life. Even if AD pathogenesis is still subject of debate, it is generally accepted that cerebral cortex plaques formed by aggregated amyloid-ß (Aß) peptides can be considered a characteristic pathological hallmark. It is well known that metal ions play an important role in the aggregation process of Aß. METHODS: This review focuses on the anti-Aß aggregation activity of chelating ligands as well as on the use of metal complexes as diagnostic probes and as potential drugs. CONCLUSION: While chelating agents, such as curcumin or flavonoid derivatives, are currently used to capture metal ions responsible for Aß aggregation, the potential application of platinum, ruthenium and cobalt complexes, among others, of several heterocyclic ligands, represents a promising new strategy to fight AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Complexos de Coordenação/farmacologia , Metais Pesados/farmacologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Complexos de Coordenação/química , Complexos de Coordenação/uso terapêutico , Humanos , Metais Pesados/química , Metais Pesados/uso terapêutico , Agregados Proteicos/efeitos dos fármacos
19.
J Inorg Biochem ; 161: 115-21, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27230387

RESUMO

Novel nickel(II) (1) and zinc(II) (2) complexes of a Salen-like ligand, carrying a pyrimidine ring on the N,N' bridge, were synthesized and characterized. Their interaction with duplex and G-quadruplex DNA was investigated in aqueous solution through UV-visible absorption, circular dichroism and viscometry measurements. The results obtained point out that, while the zinc(II) complex does not interact with both duplex and G-quadruplex DNA, the nickel(II) complex 1 binds preferentially to G-quadruplex respect to duplex-DNA, with values of the DNA-binding constants, Kb, 2.6×10(5)M(-1) and 3.5×10(4)M(-1), respectively. Molecular dynamics simulations provided an atomic level model of the top-stacking binding occurring between 1 and hTelo (a 22-mer sequence oligonucleotide) in G-quadruplex conformation.


Assuntos
DNA/química , Quadruplex G , Modelos Moleculares , Níquel/química , Zinco/química , Bases de Schiff/química
20.
J Phys Chem B ; 120(12): 3113-21, 2016 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-26943487

RESUMO

We report on the comparison between the computational and experimental determination of electronic circular dichroism spectra of different guanine quadruplexes obtained from human telomeric sequences. In particular the difference between parallel, antiparallel, and hybrid structures is evidenced, as well as the induction of transitions between the polymorphs depending on the solution environment. Extensive molecular dynamics simulations (MD) are used to probe the conformational space of the different quadruplexes, and subsequently state-of-the-art hybrid quantum mechanics/molecular mechanics (QM/MM) techniques coupled with excitonic semiempirical Hamiltonian are used to simulate the macromolecular induced circular dichroism. The coupling of spectroscopy and molecular simulation allows an efficient one-to-one mapping between structures and optical properties, offering a way to disentangle the rich, yet complicated, quantity of information embedded in circular dichroism spectra. We show that our methodology is robust and efficient and allows us to take into account subtle conformational changes. As such, it could be used as an efficient tool to investigate structural modification upon DNA/drug interactions.


Assuntos
DNA/química , Quadruplex G , Simulação de Dinâmica Molecular , Dicroísmo Circular , Humanos , Conformação de Ácido Nucleico , Teoria Quântica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA