Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 12 de 12
Filter
Add more filters










Publication year range
1.
Clin Microbiol Infect ; 21(1): 103.e1-6, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25636934

ABSTRACT

We characterized maraviroc susceptibility of dual/mixed tropic viruses from subjects enrolled onto phase IIb study A4001029. Maraviroc baseline plasma samples from 13 multidrug-experienced subjects were sequenced and the HIV-1-env gene cloned into pNL4.3Δenv to obtain recombinant viruses. The V3 region was sequenced by the Sanger method and ultradeep sequencing. By analysing subjects having a weighted optimized background therapy susceptibility (wOBT) score of <1, 3/7 subjects were characterized by good in vivo and in vitro response to maraviroc therapy. Molecular docking simulations allowed us to rationalize the maraviroc susceptibility of dual/mixed tropic viruses. A subset of subjects with dual/mixed tropic viruses responded to maraviroc. Further investigations are warranted of CCR5 antagonists in subjects carrying dual/mixed tropic virus that explore the feasible use of maraviroc in subjects that is potentially larger than those infected with a pure R5 virus.


Subject(s)
CCR5 Receptor Antagonists/pharmacology , Cyclohexanes/pharmacology , HIV Infections/virology , HIV-1/drug effects , Triazoles/pharmacology , HIV Infections/epidemiology , HIV-1/genetics , Humans , Maraviroc , Mutation/genetics , Viral Tropism
2.
Antimicrob Agents Chemother ; 58(5): 2781-97, 2014 May.
Article in English | MEDLINE | ID: mdl-24590484

ABSTRACT

Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed the NS5B polymerase genetic variability in circulating HCV genotypes/subtypes and its impact on the genetic barrier for the development of resistance to clinically relevant nucleoside inhibitors (NIs)/nonnucleoside inhibitors (NNIs). The study included 1,145 NS5B polymerase sequences retrieved from the Los Alamos HCV database and GenBank. The genetic barrier was calculated for drug resistance emergence. Prevalence and genetic barrier were calculated for 1 major NI and 32 NNI resistance variants (13 major and 19 minor) at 21 total NS5B positions. Docking calculations were used to analyze sofosbuvir affinity toward the diverse HCV genotypes. Overall, NS5B polymerase was moderately conserved among all HCV genotypes, with 313/591 amino acid residues (53.0%) showing ≤1% variability and 83/591 residues (14.0%) showing high variability (≥25.1%). Nine NNI resistance variants (2 major variants, 414L and 423I; 7 minor variants, 316N, 421V, 445F, 482L, 494A, 499A, and 556G) were found as natural polymorphisms in selected genotypes. In particular, 414L and 423I were found in HCV genotype 4 (HCV-4) (n = 14/38, 36.8%) and in all HCV-5 sequences (n = 17, 100%), respectively. Regardless of HCV genotype, the 282T major NI resistance variant and 10 major NNI resistance variants (316Y, 414L, 423I/T/V, 448H, 486V, 495L, 554D, and 559G) always required a single nucleotide substitution to be generated. Conversely, the other 3 major NNI resistance variants (414T, 419S, and 422K) were associated with a different genetic barrier score development among the six HCV genotypes. Sofosbuvir docking analysis highlighted a better ligand affinity toward HCV-2 than toward HCV-3, in agreement with the experimental observations. The genetic variability among HCV genotypes, particularly with the presence of polymorphisms at NNI resistance positions, could affect their responsiveness to NS5B inhibitors. A pretherapy HCV NS5B sequencing could help to provide patients with the full efficacy of NNI-containing regimens.


Subject(s)
Hepacivirus/genetics , Antiviral Agents/pharmacology , Genotype , Hepacivirus/drug effects , Mutation , Polymorphism, Genetic/genetics , Protein Structure, Secondary , Sofosbuvir , Uridine Monophosphate/analogs & derivatives , Uridine Monophosphate/pharmacology , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
3.
Eur J Med Chem ; 45(10): 4490-8, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20702005

ABSTRACT

Some differently substituted 3-aryl-4,5-dihydropyrazoles-1-carbothioamides have been synthesised with the aim to investigate their monoamine oxidase inhibitory activity. The chemical structures of the compounds have been characterized by means of their IR, (1)H NMR, (13)C NMR spectroscopic data and elemental analyses. All the active compounds showed a selective activity towards the B isoform of the enzyme, regardless of the substitution on the heterocyclic ring. The inhibition of the enzymatic activity was measured on human recombinant MAO isoforms, expressed in baculovirus infected BTI insect cells. Docking experiments were carried out with the aim to rationalize the mechanism of inhibition of the most active and selective compound.


Subject(s)
Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Thioamides/chemistry , Thioamides/pharmacology , Animals , Cell Line , Humans , Insecta , Models, Molecular , Monoamine Oxidase Inhibitors/chemical synthesis , Protein Binding , Pyrazoles/chemical synthesis , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity Relationship , Thioamides/chemical synthesis
4.
Endocr Relat Cancer ; 15(2): 499-510, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18509002

ABSTRACT

In this study, we evaluated the activity of two novel pyrazolopyrimidine derivatives (Si 34 and Si 35) against ARO cells, a human anaplastic thyroid cancer cell line. ARO cells exposed to different concentrations of the drugs showed a reduced growth rate and an increase of mortality. After 72 h incubation, doses of 5 and 10 microM Si 34 determined a decrease of cell counts by approximately 25% and approximately 75% compared with those of control cells respectively. Similar findings were observed using Si 35. Treatment with both Si 34 and Si 35 at 10 microM increased cell mortality also ( approximately 29% and approximately 18% respectively). At these concentrations, a decrease in cyclin D1 levels was observed. To improve the biopharmaceutical properties, a liposome formulation was prepared. When entrapped in unilamellar liposomes, Si 34 exerted its cytotoxic effects even at lower doses (maximal inhibition at 5 microM) and after shorter incubation time (48 h) either in ARO or other thyroid cancer cell lines. The effects were associated with weak apoptotic death. Inhibition of epidermal growth factor-stimulated src and ERK phosphorylation, as well as reduction of migration properties of ARO cells was also observed. Moreover, the growth of tumor xenografts induced in severe combined immunodeficiency (SCID) mice was inhibited by i.v. administration of 25-50 mg/kg of the drug liposomal formulation. In conclusion, the liposomal preparation of this novel pyrazolopyrimidine derivative appears to be a promising tool for the treatment of anaplasic thyroid cancer.


Subject(s)
Liposomes/pharmacokinetics , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Thyroid Neoplasms/drug therapy , Triazoles/pharmacokinetics , Animals , Annexin A5/metabolism , Apoptosis/drug effects , Cell Division/drug effects , Cell Line, Tumor , Humans , In Vitro Techniques , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Invasiveness , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , STAT1 Transcription Factor/drug effects , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Triazoles/chemical synthesis , Xenograft Model Antitumor Assays
5.
SAR QSAR Environ Res ; 18(5-6): 595-602, 2007.
Article in English | MEDLINE | ID: mdl-17654339

ABSTRACT

The potent herbicide paraquat and three other analogues MPP+, MPDP+ and MPTP have a known toxicological profile linked to the ability to damage dopaminergic neurons. Other biological effects were recently addressed to this class of compounds, including the ability to interact with enzymatic targets involved in the Central Nervous System, such as the acetylcholinesterase (AChE) and the butyrylcholinesterase (BuChE). A combined molecular modelling and enzymatic study focusing onto their interaction against the AChE and BuChE is reported. The former study was performed by docking techniques using target known co-crystallographic models. The latter study was carried out by the widely adopted Ellman's method. In both studies the anti-Alzheimer FDA approved drug tacrine was used as reference inhibitor. Our results indicate that paraquat, MPTP, MPDP+ and MPP+ recognize both enzymatic cleft in a similar fashion compared to the reference inhibitor. A structure-activity correlation was found with the net charge of the ligands, indicating a major role of the electrostatic term in the recognition and inhibition of these compounds. Our data completed their enzymatic profile, added new information on the molecular mechanisms underlying their neurotoxicity useful for the rational design of new cholinesterase inhibitors.


Subject(s)
Acetylcholinesterase/chemistry , Butyrylcholinesterase/chemistry , Cholinesterase Inhibitors/chemistry , Herbicides/chemistry , Models, Molecular , Paraquat/chemistry , Binding Sites , Ligands , Paraquat/analogs & derivatives , Structure-Activity Relationship
6.
J Comput Chem ; 28(6): 1119-28, 2007 Apr 30.
Article in English | MEDLINE | ID: mdl-17279500

ABSTRACT

The purpose of this work is to apply the global molecular interaction evaluation ("Glob-MolInE") computational protocol to the study of two molecular complexes characterized by a chiral selector and a couple of enantiomeric selectands experimentally known to give large difference in the free energy of complexation much higher than the experimental error normally associated to the molecular mechanic calculations. We have considered the well known diastereomeric complexes between the selector (S)-N-(3,5-dinitrobenzoyl)-leucine-n-propylamide (S)-1 and the selectands (R) or (S)-N-(2-naphthyl)-alanine methyl ester 2, widely studied by enantioselective HPLC, NMR and X-ray. The experimental difference of free energy of complexation between [(S)-1*(R)-2] and [(S)-1*(S)-2] (-1.34 kcal/mol) was reproduced by the new computational protocol with an excellent confidence error. Detailed results about the conformational search, the "quasi-flexible" docking and the thermodynamic estimation are presented in this work. A remarkable correlation between the theoretical results and experimental data (NOE measurements, X-ray crystallographic structure of the [(S)-1*(S)-2] complex and the free energy of complexation) supports the validity of the computational approach and underline the importance of the conformational multiplicity in the definition of the macroscopic properties of the complex in solution.


Subject(s)
Magnetic Resonance Spectroscopy , Mathematical Computing , Models, Chemical , Organic Chemicals/chemistry , Algorithms , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Stereoisomerism , Thermodynamics
7.
J Biotechnol ; 128(4): 908-18, 2007 Mar 10.
Article in English | MEDLINE | ID: mdl-17321623

ABSTRACT

Candida rugosa lipase crude preparations (CRL) catalyse the regioselective acylation of methyl 6-O-trytil beta-d-glucopyranoside in organic solvents, using vinyl acetate as acyl donor. The ratio of the two products formed, namely methyl 2-O acetyl 6-O-trytil beta-d-glucopyranoside and methyl 3-O acetyl 6-O-trytil beta-d-glucopyranoside was found to be markedly affected by the nature of the reaction medium. In hydrophobic solvents values up to 80% of the monoacetylated product in position C-3 were obtained compared to less than 30% in solvents with low hydrophobicity. Computational studies were carried out to simulate the interactions between methyl 6-O-trytil beta-d-glucopyranoside and both CRL and the solvents, in order to rationalize the experimental results.


Subject(s)
Candida/enzymology , Glucosides/metabolism , Lipase/metabolism , Models, Molecular , Acylation , Hydrophobic and Hydrophilic Interactions , Solvents/chemistry , Vinyl Compounds/metabolism
8.
Bioorg Med Chem ; 12(7): 1781-91, 2004 Apr 01.
Article in English | MEDLINE | ID: mdl-15028268

ABSTRACT

Novel 9-fluoren-beta-O-glycosides, designed as DNA-intercalating agents in structural correlation with antiviral tilorone and anticancer anthracyclines, have been prepared with yields in beta-anomers ranging between 25 and 63%. They have been screened for antiproliferative, immunostimulating and antiviral properties against HSV-1 and HSV-2 viruses. Compounds displaying significant antiviral activity against HSV-2 are acetylated 1 and deprotected 6 9-fluorenyl-O-d-arabinopyranoses, whereas 9-fluorenyl-O-d-glucopyranose 3 is the most effective on HSV-1 replication, followed by 1 and 6. The conformational properties of these compounds have been evaluated by molecular modelling techniques.


Subject(s)
Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Drug Design , Intercalating Agents/pharmacology , Interferons/biosynthesis , Nucleosides/pharmacology , Antineoplastic Agents/chemical synthesis , Antiviral Agents/chemical synthesis , Cell Line , DNA/drug effects , Drug Screening Assays, Antitumor , Herpesvirus 1, Human/drug effects , Herpesvirus 2, Human/drug effects , Humans , Intercalating Agents/chemical synthesis , Models, Molecular , Molecular Structure , Nucleosides/chemical synthesis , Structure-Activity Relationship , Viral Plaque Assay
9.
Bioorg Med Chem ; 11(6): 999-1006, 2003 Mar 20.
Article in English | MEDLINE | ID: mdl-12614885

ABSTRACT

Anti-inflammatory/analgesic 3,3'-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] 1, obtained as racemic mixtures (a) and mesoforms (b), have two equivalent stereogenic centres (C-2 and C-2') and exist as RR, SS and RS isomers. The enantioseparation of 1a provided the single enantiomers that displayed different in vitro cyclooxygenase-1/cyclooxygenase-2 selectivity ratios. In particular the dextrorotatory compound is a highly selective COX-2 inhibitor and the levorotatory one is moderately selective. Instead, RS-meso isomer (1b) exhibited similar levels of inhibitory activity on both COX isozymes. The diastereo- and enantioselectivity has been explained by molecular modelling of RR, SS and RS compounds into COX-1 and COX-2 binding sites. Theoretical results indicated SS>RS>RR affinity order towards COX-2 isoenzyme, in agreement with in vitro and previous in vivo pharmacological results.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Binding Sites , Chemical Phenomena , Chemistry, Physical , Crystallography, X-Ray , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Humans , In Vitro Techniques , Isoenzymes/chemistry , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Membrane Proteins , Models, Molecular , Monocytes/drug effects , Prostaglandin-Endoperoxide Synthases/chemistry , Protein Conformation , Stereoisomerism , Structure-Activity Relationship , Substrate Specificity , Thromboxane B2/antagonists & inhibitors
10.
SAR QSAR Environ Res ; 14(5-6): 475-84, 2003.
Article in English | MEDLINE | ID: mdl-14758989

ABSTRACT

Molecular mechanics (MM) and dynamics (MD) calculations in vacuo and in water have been performed for the natural cyclodepsipeptides Dolastatins 11 and 12 isolated from the sea hare Dolabella auricularia. The analysis of the MD trajectories for the two systems can give useful insight on the backbone structural features, side-chain and peptide-water interactions as well as on the inter- and intra-molecular hydrogen bonds. A comparison between the selected and analysed lowest energy isomers shows the different conformational behaviour of the compounds. Finally, with the aim to ascertain a structure-activity relationship for the two peptides, the interactions of both Dolastatins with water, generic hydrophobic environment, magnesium and calcium ions have been investigated by means of the GRID program.


Subject(s)
Depsipeptides , Models, Theoretical , Oligopeptides/chemistry , Peptides, Cyclic/chemistry , Hydrogen Bonding , Molecular Conformation , Water
11.
Bioorg Med Chem Lett ; 11(17): 2273-7, 2001 Sep 03.
Article in English | MEDLINE | ID: mdl-11527713

ABSTRACT

A preliminary MMFF implementation of selenium atom parameters necessary to model the nucleoside 1 is reported. X-ray structures of two compounds 1 and 2 have been used as references. Ab initio methods have been adopted for checking torsional energy profile and charge distribution. Monte Carlo calculations and energy minimization in solvation complete the conformational search.


Subject(s)
Antisense Elements (Genetics)/chemistry , Nucleotides/chemistry , Organometallic Compounds/chemistry , Crystallography, X-Ray , Models, Molecular , Monte Carlo Method , Nucleic Acid Conformation , Selenium/chemistry , Static Electricity
12.
J Med Chem ; 43(15): 2783-8, 2000 Jul 27.
Article in English | MEDLINE | ID: mdl-10956185

ABSTRACT

A computational model for the covalent interstrand DNA cross-linking of the antitumor agent azinomycin B is reported and is based on Monte Carlo simulations of the four possible monoalkylation species and an examination of the low energy conformations of the cross-linked agent. The model was developed using a suitably modified version of the AMBER* force field with the experimentally determined triplet DNA target sequence 5'-d(GCT)-3' in both the native B-form and containing a preformed intercalation site.


Subject(s)
Anti-Bacterial Agents/chemistry , Antibiotics, Antineoplastic/chemistry , Cross-Linking Reagents/chemistry , DNA/chemistry , Glycopeptides , Intercalating Agents/chemistry , Intercellular Signaling Peptides and Proteins , Models, Molecular , Naphthalenes , Peptides
SELECTION OF CITATIONS
SEARCH DETAIL
...