A5060221151- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Carbohydrate Chemistry and Synthesis
- Lysosomal Storage Disorders Research
- Enzyme Structure and Function
- Glycosylation and Glycoproteins Research
- Ubiquitin and proteasome pathways
- Monoclonal and Polyclonal Antibodies Research
- Amino Acid Enzymes and Metabolism
- RNA and protein synthesis mechanisms
- Synthesis and Characterization of Heterocyclic Compounds
- Oxidative Organic Chemistry Reactions
- Synthesis of Tetrazole Derivatives
- Epigenetics and DNA Methylation
- Drug Transport and Resistance Mechanisms
- RNA modifications and cancer
- Peptidase Inhibition and Analysis
- Epoxy Resin Curing Processes
- Synthesis of Organic Compounds
- CAR-T cell therapy research
- HER2/EGFR in Cancer Research
- Microbial Natural Products and Biosynthesis
- Click Chemistry and Applications
- Synthesis and biological activity
- Neuropeptides and Animal Physiology
Universitat Politècnica de Catalunya
2017-2019
Barcelona Supercomputing Center
2017-2019
Consejo Superior de Investigaciones Científicas
2010-2014
Institute of Advanced Chemistry of Catalonia
2011-2014
Universitat de Barcelona
2010-2014
Lehman College
1978
City University of New York
1978
Machine learning-based protein structure prediction algorithms, such as RosettaFold and AlphaFold2, have greatly impacted the structural biology field, arousing a fair amount of discussion around their potential role in drug discovery. While there are few preliminary studies addressing usage these models virtual screening, none them focus on prospect hit-finding real-world screen with model based low prior information. In order to address this, we developed an AlphaFold2 version where...
We present the results for CAPRI Round 46, third joint CASP-CAPRI protein assembly prediction challenge. The comprised a total of 20 targets including 14 homo-oligomers and 6 heterocomplexes. Eight homo-oligomer one heterodimer proteins that could be readily modeled using templates from Protein Data Bank, often available full assembly. remaining 11 5 homodimers, 3 heterodimers, two higher-order assemblies. These were more difficult to model, as their mainly involved "ab-initio" docking...
The availability of AlphaFold2 has led to great excitement in the scientific community─particularly among drug hunters─due ability algorithm predict protein structures with high accuracy. However, beyond globally accurate structure prediction, it remains be determined whether ligand binding sites are predicted sufficient accuracy these useful supporting computationally driven discovery programs. We explored this question by performing free-energy perturbation (FEP) calculations on a set...
L-amino acid transporters (LATs) play key roles in human physiology and are implicated several pathologies. LATs asymmetric amino exchangers where the low apparent affinity cytoplasmic side controls exchange of substrates with high on extracellular side. Here, we report crystal structures an LAT, bacterial alanine-serine-cysteine exchanger (BasC), a non-occluded inward-facing conformation both apo substrate-bound states. We crystallized BasC complex nanobody, which blocks transporter from...
Abstract Recent cryoEM studies elucidated details of the structural basis for substrate selectivity and translocation heteromeric amino acid transporters. However, Asc1/CD98hc is only neutral transporter that can function through facilitated diffusion, one efficiently transports glycine D-serine, thus has a regulatory role in central nervous system. Here we use cryoEM, ligand-binding simulations, mutagenesis, transport assays, molecular dynamics to define human determinants specificity gain...
New N-alkylaminocyclitols bearing a 1,2,3-triazole system at different positions of the alkyl chain have been prepared as potential GCase pharmacological chaperones using click chemistry approaches. Among them, compounds 1d and 1e, with shorter spacer (n = 1) between alkyltriazolyl aminocyclitol core, were most active ones inhibitors, revealing determinant effect location triazole ring on activity. Furthermore, SAR data computational docking models indicate correlation lipophilicity enzyme...
A library of aminocyclitols derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series azides [1−25] is described tested against GCase. Azides have been chosen large collection potential candidates that has filtered according to physical reactivity constraints. synthetic methodology optimized in order avoid the use protecting groups on aminocyclitol scaffold. Because can be carried out an aqueous system, resulting members screened situ with minimal manipulation. From...
Engineered scaffold-based proteins that bind to concrete targets with high affinity offer significant advantages over traditional antibodies in theranostic applications. Their development often relies on display methods, where large libraries of variants are physically contacted the desired target protein and pools binding can be selected. Herein, we use a combined artificial intelligence/physics-based computational framework phage approach obtain ubiquitin based Affilin ® targeting HER3...
Abstract PROTACs (Proteolysis-Targeting Chimeras) have emerged as a powerful modality for targeted protein degradation, yet their optimization still relies heavily on trial-and-error methods. A key factor in PROTAC degradation efficiency is the formation of ternary complex (TC) between and its target proteins. However, due to dynamic nature, PROTAC-mediated TCs can adopt multiple conformations, making characterization challenging. Computational methods that account this flexibility provide...
Engineered scaffold-based proteins that bind to concrete targets with high affinity offer significant advantages over traditional antibodies in theranostic applications. Their development often relies on display methods, where large libraries of variants are physically contacted the desired target protein and pools binding can be selected. Herein, we use a novel combined artificial intelligence/physics-based computational framework phage approach obtain ubiquitin based Affilin® targeting...
Significance The transport of amino acids across the plasma membrane plays a central role in physiology. heteromeric acid transporters (HATs) neutral (LAT1/CD98hc, LAT2/CD98hc, and Asc1/CD98hc) participate variety processes such as modulation glutamatergic neurotransmission synaptic plasticity, auditory function, promotion brain development tumor growth by supporting mTORC1 activity. We identify substrate specificity determinants HATs within substrate-binding cavity nearby region that holds...
Aminocyclitols comprise an important group of compounds with remarkable biological activities. From a structural standpoint, aminocyclitols are amino polyhydroxy cycloalkanes that can be found in nature several families natural products. Among them, the aminoglycoside antibiotics, since discovery streptomycin, have become particularly relevant at forefront antibacterial treatment. Another aminocyclitols, generally referred to as aminocarbasugars, been key components some alkaloids evolved...
ABSTRACT The availability of AlphaFold2 has led to great excitement in the scientific community - particularly among drug hunters due ability algorithm predict protein structures with high accuracy. However, beyond globally accurate structure prediction, it remains be determined whether ligand binding sites are predicted sufficient accuracy these useful supporting computationally driven discovery programs. We explored this question by performing free energy perturbation (FEP) calculations on...
p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of signaling has been linked several diseases including inflammation, immune disorders cancer, suggesting targeting could be therapeutically beneficial. Over last two decades, inhibitors have developed, which showed promising effects pre-clinical studies but results from clinical trials disappointing, fueling interest generation alternative...
Glucocerebrosidase (GCase, acid β-Glucosidase) hydrolyzes the sphingolipid glucosylceramide into glucose and ceramide. Mutations in this enzyme lead to a lipid metabolism disorder known as Gaucher disease. The design of competitive inhibitors GCase is promising field research for pharmacological chaperones new therapeutic agents. Using series recently reported molecules with experimental binding affinities nanomolar micromolar range, we here report an extensive theoretical analysis their...
Abstract A series of hybrid analogues was designed by combination the iminoxylitol scaffold parent 1C9‐DIX with triazolylalkyl side chains. The resulting compounds were considered potential pharmacological chaperones in Gaucher disease. DIX reported here synthesized CuAAC click chemistry from 1 (α‐1‐ C ‐propargyl‐1,5‐dideoxy‐1,5‐imino‐ D ‐xylitol) and screened as imiglucerase inhibitors. set selected tested β‐glucocerebrosidase (GBA1) enhancers fibroblasts patients bearing different...
Traditional drug discovery programs are being transformed by the advent of machine learning methods. Among these, Generative AI methods (GM) have gained attention due to their ability design new molecules and enhance specific properties existing ones. However, current GM limitations, such as low affinity towards target, unknown ADME/PK properties, or lack synthetic tractability. To improve applicability domain methods, we developed a workflow based on variational autoencoder coupled with...
In silico binding site location and pose prediction for a molecule targeted at large protein surface is challenging task. We report blind test with two peptidomimetic molecules that bind the flu virus hemagglutinin (HA) antigen, JNJ7918 JNJ4796 (recently disclosed in van Dongen et al., Science, 2019, 363). Tests series of conventional approaches such as rigid (receptor) docking against available X-ray crystal structures or an ensemble generated by quick methodologies (NMA, homology modeling)...
Abstract Machine learning protein structure prediction, such as RosettaFold and AlphaFold2, have impacted the structural biology field, raising a fair amount of discussion around its potential role in drug discovery. While we find some preliminary studies addressing usage these models virtual screening, none them focus on prospect hit-finding real-world screen with target low sequence identity. In order to address this, developed an AlphaFiold2 version where exclude all templates more than...
Metallocarboxypeptidase D (CPD) is a membrane-bound component of the trans-Golgi network that cycles to cell surface through exocytic and endocytic pathways. Unlike other members metallocarboxypeptidase family, CPD multicatalytic enzyme with three carboxypeptidase-like domains, although only first two domains are predicted be enzymatically active. To investigate enzymatic properties each domain in human CPD, critical active site Glu I and/or II was mutated Gln protein expressed, purified,...
Abstract The seventh CAPRI edition imposed new challenges to the modeling of protein‐protein complexes, such as multimeric oligomerization, protein‐peptide, and protein‐oligosaccharide interactions. Many proposed targets needed efficient integration rigid‐body docking, template‐based modeling, flexible optimization, multiparametric scoring, experimental restraints. This was especially relevant for multimolecular assemblies in CASP12‐CAPRI37 CASP13‐CAPRI46 joint rounds, which were described...
An efficient method for the preparation of novel 3-alkyl- and 3-aryl-4-iodophenols from 3-arylphenols is described.
SUMMARY SETD8 is a methyltransferase that overexpressed in several cancers, which monomethylates H4K20 as well other non-histone targets such PCNA or p53. We here report novel inhibitors, were discovered while trying to identify chemicals prevent 53BP1 foci formation, an event mediated by methylation. Consistent with previous reports, inhibitors induce p53 expression, although they are equally toxic for p53-deficient cells. Thermal stability proteomics revealed the compounds had particular...