Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 13 de 13
Filter
Add more filters










Publication year range
1.
Comput Biol Chem ; 72: 122-135, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29274684

ABSTRACT

In this study, a virtual screening procedure was applied to identify new potential nt-MGAM inhibitors as a possible medication for type 2 diabetes. To this aim, a series of salacinol analogues were first investigated by docking analysis for their binding to the X-ray structure of the biological target nt-MGAM. Key interactions for ligand binding into the receptor active site were identified which shared common features to those found for other known inhibitors, which strengthen the results of this study. 3D QSAR model was then built and showed to be statistically significant and with a good predictive power for the training (R2 = 0.99, SD = 0.17, F = 555.3 and N = 27) and test set (Q2 = 0.81, Pearson(r) = 0.92, RMSE = 0.52, N = 08). The model was then used to virtually screen the ZINC database with the aim of identifying novel chemical scaffolds as potential nt-MGAM inhibitors. Further, in silico predicted ADME properties were investigated for the most promising molecules. The outcome of this investigation sheds light on the molecular characteristics of the binding of salacinol analogues to nt-MGAM enzyme and identifies new possible inhibitors which have the potential to be developed into drugs, thus significantly contributing to the design and optimization of therapeutic strategies against type 2 diabetes.


Subject(s)
Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/chemistry , Sugar Alcohols/chemistry , Sulfuric Acid Esters/chemistry , alpha-Glucosidases/chemistry , Diabetes Mellitus, Type 2/drug therapy , Drug Evaluation, Preclinical , Hydrogen Bonding , Ligands , Molecular Docking Simulation , Quantitative Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 27(15): 3332-3336, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28610983

ABSTRACT

In the last ten years, we identified and developed a new therapeutic class of antifungal agents, the macrocyclic amidinoureas. These compounds are active against several Candida species, including clinical isolates resistant to currently available antifungal drugs. The mode of action of these molecules is still unknown. In this work, we developed an in-silico target fishing procedure to identify a possible target for this class of compounds based on shape similarity, inverse docking procedure and consensus score rank-by-rank. Chitinase enzyme emerged as possible target. To confirm this hypothesis a novel macrocyclic derivative has been produced, specifically designed to increase the inhibition of the chitinase. Biological evaluation highlights a stronger enzymatic inhibition for the new derivative, while its antifungal activity drops probably because of pharmacokinetic issues. Collectively, our data suggest that chitinase represent at least one of the main target of macrocyclic amidinoureas.


Subject(s)
Antifungal Agents/pharmacology , Chitinases/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Trichoderma/drug effects , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Chitinases/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Trichoderma/enzymology
3.
Bioorg Med Chem Lett ; 27(11): 2502-2505, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28408224

ABSTRACT

AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds. These derivatives have the dual action required inhibiting HIV replication in human TZM-bl cells infected with HIV-1 NL4.3 and showing cytotoxic activity on human colon HT-29 and breast adenocarcinoma MCF-7 cells. In addition, preclinical in vitro adsorption, distribution, metabolism, and excretion studies highlighted a satisfactory pharmacokinetic profile.


Subject(s)
Anti-Retroviral Agents/chemistry , Anti-Retroviral Agents/metabolism , Anti-Retroviral Agents/pharmacology , Anti-Retroviral Agents/toxicity , Cell Survival/drug effects , Gene Expression/drug effects , HIV-1/drug effects , HT29 Cells , Humans , MCF-7 Cells , Microsomes, Liver/metabolism , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Telomerase/genetics , Telomerase/metabolism
4.
Eur J Med Chem ; 121: 169-180, 2016 Oct 04.
Article in English | MEDLINE | ID: mdl-27240272

ABSTRACT

The development of new anti-tubercular agents represents a constant challenge mostly due to the insurgency of resistance to the currently available drugs. In this study, a set of 60 molecules were selected by screening the Asinex and the ZINC collections and an in house library by means of in silico ligand-based approaches. Biological assays in Mycobacterium tuberculosis H37Ra ATCC 25177 strain highlighted (±)-1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethyl-4-(3,4-dichlorophenyl)piperazine-1-carboxylate (5i) and 3-(4-chlorophenyl)-5-(2,4-dimethylpyrimidin-5-yl)-2-methylpyrazolo[1.5-a]pyrimidin-7(4H)-one (42) as the most potent compounds, having a Minimum Inhibitory Concentration (MIC) of 4 and 2 µg/mL respectively. These molecules represent a good starting point for further optimization of effective anti-TB agents.


Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Computer Simulation , Drug Discovery , Ligands , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Small Molecule Libraries
5.
J Med Chem ; 59(8): 3854-66, 2016 04 28.
Article in English | MEDLINE | ID: mdl-27045868

ABSTRACT

We recently identified a novel family of macrocyclic amidinoureas showing potent antifungal activity against Candida spp. In this study, we demonstrate the fungicidal effect of these compounds as well as their killing activity in a dose-dependent manner. Transcriptional analysis data indicate that our molecules induce a significant change in the transcriptome involving ATP binding cassette (ABC) transporter genes. Notably, experiments against Candida albicans mutants lacking those genes showed resistance to the compound, suggesting the involvement of ABC transporters in the uptake or intracellular accumulation of the molecule. To probe the mode of action, we performed fluorescence microscopy experiments on fungal cells treated with an ad-hoc synthesized fluorescent derivative. Fluorescence microscopy images confirm the ability of the compound to cross the membrane and show a consistent accumulation within the cytoplasm. Finally, we provide data supporting the in vivo efficacy in a systemic infection murine model setup with a drug-resistant strain of C. albicans.


Subject(s)
Antifungal Agents/pharmacology , Macrocyclic Compounds/pharmacology , Yeasts/drug effects , Animals , Antifungal Agents/chemistry , Colony Count, Microbial , Macrocyclic Compounds/chemistry , Mice , Microbial Sensitivity Tests , Microscopy, Fluorescence , Yeasts/isolation & purification
6.
Bioorg Med Chem Lett ; 24(23): 5525-9, 2014 Dec 01.
Article in English | MEDLINE | ID: mdl-25455183

ABSTRACT

Antibiotic resistance has reached alarming levels in many clinically-relevant human pathogens, and there is an increasing clinical need for new antibiotics active on drug-resistant Gram-negative pathogens who rapidly evolve towards pandrug resistance phenotypes. Here, we report on two related classes of guanidinic compounds endowed with antibacterial activity. The two best compounds (9a and 13d) exhibited the most potent antibacterial activity with MIC values ranging 0.12-8 µg/ml with most tested pathogens, including both Gram-positive and Gram-negative bacteria. Interestingly, MIC values were not affected (1-8 µg/ml) when measured using recent clinical isolates with various antibiotic resistance determinants. The results reported herein identify guazatine derivatives as an interesting starting point for the optimization of a potentially novel class of antibacterial agents.


Subject(s)
Anti-Bacterial Agents/pharmacology , Guanidines/chemistry , Drug Resistance, Microbial , Humans , Microbial Sensitivity Tests
7.
J Chem Theory Comput ; 9(1): 698-706, 2013 Jan 08.
Article in English | MEDLINE | ID: mdl-26589066

ABSTRACT

Several pieces of experimental evidence led us to hypothesize that the mechanism of action of paclitaxel (Taxol) could involve a two-steps binding process, with paclitaxel first binding within the outer wall of microtubules and then moving into the inner binding site. In this work, we first used multiply targeted molecular dynamics (MTMD) for steering paclitaxel from the outer toward the inner binding site. This rough trajectory was then submitted to a refinement procedure in the path collective variables space. Paclitaxel binding energy was monitored along the refined pathway, highlighting the relevance of residues belonging to the H6-H7 and the M- loops. Computational results were supported by kinetics studies performed on fluorescent paclitaxel derivatives.

8.
Bioorg Med Chem ; 20(1): 234-42, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-22137934

ABSTRACT

The synthesis, cytotoxicity, inhibition of tubulin polymerization data and anti-angiogenetic effects of seven 1,5-disubstituted 1,2,3-triazole analogs and two 1,4-disubstituted 1,2,3-triazole analogs of combretastatin A-1 (1) are reported herein. The biological studies revealed that the 1,5-disubstituted 1,2,3-triazoles 3-methoxy-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzene-1,2-diol (6), 3-methoxy-6-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)benzene-1,2-diamine (8) and 5-(2,3-difluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole (9) were the three most active compounds regarding inhibition of both tubulin polymerization and angiogenesis. Molecular modeling studies revealed that combretastatins 1 and 2 and analogs 5-11 could be successfully docked into the colchicine binding site of α,ß-tubulin.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Models, Molecular , Stilbenes/chemistry , Triazoles/chemistry , Tubulin Modulators/chemical synthesis , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Binding Sites , Cell Line , Humans , Molecular Dynamics Simulation , Polymerization/drug effects , Protein Structure, Tertiary , Triazoles/chemical synthesis , Triazoles/pharmacology , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology
9.
Bioorg Med Chem Lett ; 21(18): 5255-8, 2011 Sep 15.
Article in English | MEDLINE | ID: mdl-21807515

ABSTRACT

Trypanothione reductase (TryR) is one of the favorite targets for those designing drugs for the treatment of Chagas disease. We present the application of a fast virtual screening approach for designing hit compounds active against TryR. Our protocol combines information derived from structurally known inhibitors and from the TryR receptor structure. Five structurally diverse hit compounds active against TryR and holding promise for the treatment of Chagas disease are reported.


Subject(s)
Enzyme Inhibitors/pharmacology , High-Throughput Screening Assays , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Structure , NADH, NADPH Oxidoreductases/metabolism , Stereoisomerism , Structure-Activity Relationship
10.
Chem Biol ; 17(3): 243-53, 2010 Mar 26.
Article in English | MEDLINE | ID: mdl-20338516

ABSTRACT

The pore site in microtubules has been studied with the use of Hexaflutax, a fluorescent probe derived from paclitaxel. The compound is active in cells with similar effects to paclitaxel, indicating that the pore may be a target to microtubule stabilizing agents. While other taxanes bind microtubules in a monophasic way, thus indicating a single type of sites, Hexaflutax association is biphasic. Analysis of the phases indicates that two different binding sites are detected, reflecting two different modes of binding, which could arise from different arrangements of the taxane or fluorescein moieties in the pore. Association of the 4-4-20 antifluorescein monoclonal antibody-Hexaflutax complex to microtubules remains biphasic, thus indicating that the two phases observed arise from two different poses of the taxane moiety.


Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Microtubules/chemistry , Taxoids/chemistry , Tubulin Modulators/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Binding Sites , Humans , Kinetics , Microscopy, Confocal , Microtubules/metabolism , Models, Molecular , Taxoids/pharmacology , Thermodynamics , Tubulin Modulators/pharmacology , Tumor Cells, Cultured
11.
ACS Med Chem Lett ; 1(8): 416-21, 2010 Nov 11.
Article in English | MEDLINE | ID: mdl-24900226

ABSTRACT

Three simplified "non-natural" natural taxanes, related to taxuspine X, were synthetized and assayed as P-glycoprotein (P-gp) inhibitors. One of them (6) proved to be a very efficient P-gp inhibitor with an IC50 = 7.2 × 10(-6) M. In addition, to rationalize biological data, a pharmacophoric model was built through a ligand-based approach. This model represents the first example of a pharmacophore, which describes interactions of taxanes with P-gp.

12.
FASEB J ; 23(10): 3298-308, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19509307

ABSTRACT

In a previous investigation, we demonstrated that after CD95/Fas triggering, raft-associated GD3 ganglioside, normally localized at the plasma membrane of T cells, can be detected in mitochondria, where they contribute to apoptogenic events. Here, we show the association of the glycosphingolipid GD3 with microtubular cytoskeleton at very early time points following Fas ligation. This was assessed by different methodological approaches, including fluorescence resonance energy transfer, immunoelectron microscopy, and coimmunoprecipitation. Furthermore, docking analysis also showed that GD3 has a high affinity for the pore formed by 4 tubulin heterodimers (type I pore), thus suggesting a possible direct interaction between tubulin and GD3. Finally, time-course analyses indicated that the relocalization of GD3 to the mitochondria was time related with the alterations of the mitochondrial membrane potential. Hence, microtubules could act as tracks for ganglioside redistribution following apoptotic stimulation, possibly contributing to the mitochondrial alterations leading to cell death.


Subject(s)
Gangliosides/metabolism , Membrane Microdomains/metabolism , Microtubules/metabolism , Tubulin/metabolism , fas Receptor/metabolism , Cell Line, Tumor , Computer Simulation , Gangliosides/chemistry , Humans , Membrane Microdomains/chemistry , Mitochondria/metabolism , Models, Biological , Protein Conformation , Tubulin/chemistry , fas Receptor/chemistry
13.
FEBS J ; 276(10): 2701-12, 2009 May.
Article in English | MEDLINE | ID: mdl-19459933

ABSTRACT

Taxanes and other microtubule-stabilizing agents comprise an important class of anticancer drugs. It is well known that taxanes act by binding to beta-tubulin on the lumenal side of microtubules. However, experimental evidence obtained in recent years led to the hypothesis of an external site on the microtubule wall to which taxanes and other microtubule-stabilizing agents could bind before being internalized to their lumenal site. In the present study, different computational techniques were combined to explore the possible existence of an exposed and easily accessible binding site for microtubule-stabilizing agents on the outside of microtubules. The results obtained indicate that the conformational rearrangement of the H6-H7 hoop of beta-tubulin can form a suitable pocket on the outer microtubule surface, and that paclitaxel can efficaciously interact with this newly-proposed binding site.


Subject(s)
Microtubules/metabolism , Paclitaxel/metabolism , Tubulin/metabolism , Binding Sites , Kinetics , Models, Molecular , Tubulin/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...