A5084071049- Peptidase Inhibition and Analysis
- Cancer Treatment and Pharmacology
- Aldose Reductase and Taurine
- Microtubule and mitosis dynamics
- Protease and Inhibitor Mechanisms
- Alcohol Consumption and Health Effects
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Cancer therapeutics and mechanisms
- Bacterial Genetics and Biotechnology
- Eicosanoids and Hypertension Pharmacology
- Signaling Pathways in Disease
- Prenatal Substance Exposure Effects
- Chemical synthesis and alkaloids
- Alkaloids: synthesis and pharmacology
- Cancer, Hypoxia, and Metabolism
- Ubiquitin and proteasome pathways
- Protein Tyrosine Phosphatases
- Click Chemistry and Applications
- Viral Infections and Vectors
- Heat shock proteins research
- Enzyme function and inhibition
- Seaweed-derived Bioactive Compounds
- Glycosylation and Glycoproteins Research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
Universidad San Pablo CEU
2014-2023
Universidad San Pablo
2014-2018
Universidad de Alcalá
2008-2014
Consejo Superior de Investigaciones Científicas
2013
University College London
2011
Centro de Investigaciones Biológicas Margarita Salas
2011
The binding interactions of two antitumor agents that target the paclitaxel site, docetaxel and discodermolide, to unassembled α/β-tubulin heterodimers microtubules have been studied using biochemical NMR techniques. use discodermolide as a water-soluble biomimetic extensive experiments allowed detection microtubule-stabilizing tubulin α/β-heterodimers. bioactive 3D structures bound α/β-heterodimers were elucidated compared those microtubules, where subtle changes in conformations its...
Cyclopentenone prostaglandins (cyPG) are reactive eicosanoids that may display anti-inflammatory and antiproliferative actions, possibly offering therapeutic potential. Here we report the identification of members aldo-keto reductase (AKR) family as selective targets cyPG prostaglandin A(1) (PGA(1)). AKR enzymes metabolize aldehydes drugs containing carbonyl groups involved in inflammation tumorigenesis. Thus, these represent a class to develop small molecule inhibitors with activity....
The Vinca alkaloids are a group of widely used anticancer drugs, originally extracted from the Madagascar periwinkle, that disrupt microtubule dynamics in mammalian cells by interfering with proper assembly α,β-tubulin heterodimers. They favor curved tubulin assemblies destabilize microtubules and induce formation spiral aggregates. Their binding energy profiles have been characterized means sedimentation velocity assays site vinblastine at interface between two dimers (α1β1 – α2β2) has...
The design of multitarget drugs (MTDs) has become an innovative approach for the search effective treatments in complex diseases such as cancer. In this work, we communicate our efforts multi-targeting histone deacetylase (HDAC) and protein kinase CK2 inhibitors a novel therapeutic strategy against Using tetrabromobenzotriazole (TBB) 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT) scaffolds inhibition, hydroxamate to coordinate zinc atom present active site HDAC (zinc binding group,...
The binding of epothilones to dimeric tubulin and microtubules has been studied by means biochemical NMR techniques. We have determined the constants epothilone A (EpoA) B (EpoB) tubulin, which are 4 orders magnitude lower than those for microtubules, we elucidated conformation epitopes EpoA EpoB when bound dimers in solution. is similar that found X-ray crystallographic techniques Tubulin/RB3/TTL complex; it markedly different from reported zinc-induced sheets obtained electron...
A new series of TBB-derivatives was synthesized and characterized as CK2 inhibitors. Crystallographic analysis docking studies were used to understand the mode binding.
Drug entities able to address multiple targets can be more effective than those directed just one biological target.
Ten novel taxanes bearing modifications at the C2 and C13 positions of baccatin core have been synthesized their binding affinities for mammalian tubulin experimentally measured. The design strategy was guided by (i) calculation interaction energy maps with carbon, nitrogen oxygen probes within taxane-binding site β-tubulin, (ii) prospective use a structure-based QSAR (COMBINE) model derived from an earlier series comprising 47 congeneric taxanes. tubulin-binding affinity displayed one new...
MMP-2 is a validated target for the development of anticancer agents. Herein we describe synthesis new series potent phenylalanine derived hydroxamates, with increased MMP-2/MMP-9 selectivity compared to analogous hydroxamates described previously. Docking and molecular dynamics experiments have been used account this selectivity, clarify role triazole ring in binding process.
Four potent CK2 inhibitors derived from CX-4945 are described. They also provided nanomolar activity against HDAC1, therefore having promising utility as dual-target agents for cancer. The linker length between the hydroxamic acid and scaffold plays an important role in dictating balanced targeted enzymes. seven-carbon (compound 15c) was optimal inhibition of both HDAC1. Remarkably, 15c showed 3.0 3.5 times higher inhibitory than reference compounds (against CK2) SAHA HDAC1), respectively....
DHQ2 (type II dehydroquinase), which is an essential enzyme in Helicobacter pylori and Mycobacterium tuberculosis does not have any counterpart humans, recognized to be attractive target for the development of new antibacterial agents. Computational biochemical studies that help understand atomic detail catalytic mechanism these bacterial enzymes are reported present paper. A previously unknown key role certain conserved residues enzymes, as well structural changes responsible triggering...
Sixteen new 7′-homo-anhydrovinblastine derivatives were prepared in one or two steps from vinorelbine by means of an original and regiospecific rearrangement subsequent diastereoselective reduction. This strategy has allowed fast access to a family vinca alkaloid with enlarged functionalized ring C′. Their synthesis biological evaluation are reported. One compound (compound 35) is 1.7 times more active than as tubulin assembly inhibitor. Moreover, some these compounds highly cytotoxic, them...
Gelatinases (MMP-2 and MMP-9), a subfamily of Matrix Metalloproteinases (MMPs), are involved in several pathologies especially cancer. Thiirane is latent-zinc binding group used for the design potent inhibitors gelatinases. Here we report new family thiirane inhibitors, obtained by click chemistry. Thus, an azide fragment containing was connected to lipophilic alkynes, which were designed interact with S1′ pocket two Our hit compound (2f) displayed submicromolar inhibition MMP-2 (IC50 = 0.62...
Abstract The conformational preferences of epothilone A (EPA) and a 12,13‐cyclopropyl C12‐epimerized analogue were explored in aqueous solution using molecular dynamics simulations. simulated conformers that provided an optimal fit the paclitaxel binding site mammalian β‐tubulin then selected. resulting modeled complexes before after refinement M‐loop to improve fitting assess ligand stability within pocket. tubulin‐bound conformation EPA was found be unlike previously reported obtained...
Hybrids of vinca alkaloids and phomopsin A have been elaborated with the aim interfering "vinca site" "peptide domain in tubulin. They were synthesized by an efficient one-pot procedure that directly links octahydrophomopsin lateral chain to velbenamine moiety 7′-homo-anhydrovinblastine. In their modeled complexes tubulin, these hybrids found superimpose nicely on tubulin-bound structures vinblastine A. This good matching can account for fact two them are very potent inhibitors microtubules...
Abstract Using information from wild‐type and mutant Vibrio vulnificus nuclease (Vvn) I‐PpoI homing endonuclease co‐crystallized with different oligodeoxynucleotides, we have built the complex of Vvn a DNA octamer carried out series simulations to dissect catalytic mechanism this metallonuclease in stepwise fashion. The distinct roles played reaction by individual active site residues, metal cation water molecules been clarified using combination classical molecular dynamics quantum...
Abstract Herein we report comparative binding energy (COMBINE) analyses to derive quantitative structure–activity relationship (QSAR) models that help rationalize the determinants of affinity for inhibitors type II dehydroquinase (DHQ2), third enzyme shikimic acid pathway. Independent COMBINE were derived Helicobacter pylori and Mycobacterium tuberculosis DHQ2, which is an essential in both these pathogenic bacteria has no counterpart human cells. These studies quantify importance hydrogen...
Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new necessary. The inhibition matrix metalloproteinase MMP-13 validated strategy to prevent progression this common disorder. We recently described polybrominated benzotriazole derivatives nanomolar inhibitory activity promising selectivity profile against collagenase. In work, we have...