A5003003640- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Signaling Pathways in Disease
- Cholinesterase and Neurodegenerative Diseases
- Protein Degradation and Inhibitors
- Influenza Virus Research Studies
- Alzheimer's disease research and treatments
- Peptidase Inhibition and Analysis
- Nicotinic Acetylcholine Receptors Study
- Multiple Myeloma Research and Treatments
- Ubiquitin and proteasome pathways
- Click Chemistry and Applications
- Machine Learning in Materials Science
- Toxin Mechanisms and Immunotoxins
- Photodynamic Therapy Research Studies
- Force Microscopy Techniques and Applications
- Protein Interaction Studies and Fluorescence Analysis
- Neonatal Health and Biochemistry
- Receptor Mechanisms and Signaling
- Eicosanoids and Hypertension Pharmacology
- RNA and protein synthesis mechanisms
- HIV/AIDS drug development and treatment
- Biochemical and Structural Characterization
- Phosphodiesterase function and regulation
- Chemical synthesis and alkaloids
Universitat de Barcelona
2014-2025
University of Edinburgh
2016-2022
Interactive Scientific (United Kingdom)
2020
Institute for Biomedicine
2017
A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well monoamino oxidase (MAO) B, has been synthesized. Novel compounds (3–9) have designed using a conjunctive approach that combines the benzylpiperidine moiety AChE inhibitor donepezil (1) indolyl propargylamino MAO N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5)...
We have synthesized a family of rhein-huprine hybrids to hit several key targets for Alzheimer's disease. Biological screening performed in vitro and Escherichia coli cells has shown that these exhibit potent inhibitory activities against human acetylcholinesterase, butyrylcholinesterase, BACE-1, dual Aβ42 tau antiaggregating activity, brain permeability. Ex vivo studies with the leads (+)- (-)-7e slices C57bl6 mice revealed they efficiently protect Aβ-induced synaptic dysfunction,...
Abstract Immunotherapy promotes the attack of cancer cells by immune system; however, it is difficult to detect early responses before changes in tumor size occur. Here, we report rational design a fluorogenic peptide able picomolar concentrations active granzyme B as biomarker immune-mediated anticancer action. Through series chemical iterations and molecular dynamics simulations, synthesize library FRET peptides identify probe H5 with an optimal fit into B. We demonstrate that enables...
With innumerable clinical failures of target-specific drug candidates for multifactorial diseases, such as Alzheimer's disease (AD), which remains inefficiently treated, the advent multitarget discovery has brought a new breath hope. Here, we disclose class 6-chlorotacrine (huprine)-TPPU hybrids dual inhibitors enzymes soluble epoxide hydrolase (sEH) and acetylcholinesterase (AChE), profile to provide cumulative effects against neuroinflammation memory impairment. Computational studies...
Targeted protein degradation is a promising therapeutic strategy, spearheaded by the anti-myeloma drugs lenalidomide and pomalidomide. These stabilize very efficiently complex between E3 ligase Cereblon (CRBN) several non-native client proteins (neo-substrates), including transcription factors Ikaros Aiolos enzyme Caseine Kinase 1α (CK1α,), resulting in their degradation. Although structures for these complexes have been determined, there are no evident interactions that can account high...
Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by rapid emergence amantadine-resistant virus strains. We have synthesized and characterized a series polycyclic compounds designed as ring-contracted or ring-expanded analogues amantadine. Inhibition wild-type (wt) A/M2-S31N A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane noradamantane derivatives...
Amantadine inhibits the M2 proton channel of influenza A virus, yet most currently circulating strains virus carry mutations in protein that render amantadine-resistant. While research on novel amantadine analogues has revolved around synthesis adamantane derivatives, we have recently found other polycyclic scaffolds effectively block channel, including amantadine-resistant mutant channels. In this work, synthesized and characterized a series pyrrolidine derivatives designed as amantadine....
Drug discovery starts with the identification of a ‘hit’ compound that, following long and expensive optimization process, evolves into drug candidate. Bigger screening collections increase odds finding more better hits. For this reason, large pharmaceutical companies have invested heavily in high-throughput (HTS) that can contain several million compounds. However, figure pales comparison emergent on-demand chemical collections, which recently reached trillion scale. These are potentially...
Abstract Background The specificity of the ubiquitination process is mediated by E3 ligases. Discriminating genuine substrates E3s from mere interacting proteins one major challenges in field. We previously developed BioE3, a biotin-based approach that uses BirA-E3 fusions together with ubiquitin fused to low-affinity AviTag obtain site-specific and proximity-dependent biotinylation substrates. proved suitability BioE3 identify targets RING HECT-type Methods experiments were performed...
Abstract Background The specificity of the ubiquitination process is mediated by E3 ligases. Discriminating genuine substrates E3s from mere interacting proteins one major challenges in field. We previously developed BioE3, a biotin-based approach that uses BirA-E3 fusions together with ubiquitin fused to low-affinity AviTag obtain site-specific and proximity-dependent biotinylation substrates. proved suitability BioE3 identify targets RING HECT-type Methods experiments were performed...
Molecular simulations led to the discovery of a new class small molecules that inhibit cyclophilin family proteins.
Molecular simulations were used to design large scale loop motions in the enzyme cyclophilin A and NMR biophysical methods employed validate models.
The M2 proton channel of influenza A virus is an integral membrane protein involved in the acidification viral interior, a step necessary for release genetic material and replication new virions. aim this study to explore mechanism drug (un)binding order gain insight into structural energetic features relevant development novel inhibitors. To end, we have investigated binding amantadine (Amt) wild type (wt) its V27A variant using multiple independent molecular dynamics simulations,...
The critical role of BACE-1 in the formation neurotoxic ß-amyloid peptides brain makes it an attractive target for efficacious treatment Alzheimer's disease. However, development clinically useful inhibitors has proven to be extremely challenging. In this study we examine binding mode a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination two fragments-huprine and rhein-that individually are endowed very low activity against BACE-1. Examination crystal...
Alzheimer's disease (AD), affecting almost 50 million individuals worldwide, is currently the first cause of dementia. Despite tremendous research efforts in last decade, only four supportive or palliative drugs, namely, acetylcholinesterase (AChE) inhibitors donepezil, galantamine, and rivastigmine glutamate NMDA receptor antagonist memantine, are available. New therapeutic strategies becoming prominent, such as direct inhibition amyloid formation regulation metal homeostasis. In present...
Abstract The chemical and reaction spaces are incredibly vast special procedures required to study them. Their complex multiparametric nature encompass myriads of compounds interactions endless modifications involving the distinct impact relevant variables (temperature, solvent, stoichiometry, etc.). This often calls for design, collection, analysis/interpretation large datasets. Reaction charting, systematic scanning, description, analysis, guided a given process, stands as most promising...
Predicting the conformational preferences of flexible compounds is a challenging problem in drug design, where recognition between ligand and receptor affected by ability interacting partners to adopt favorable conformation for binding. To explore space ligands obtain relative free energy wells, we have recently reported multilevel computational strategy that relies on predominant-state approximation-where partitioned into distinct wells-and combines low-level method sampling minima...