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Ferran Sanz

Publications and source records attributed to Ferran Sanz.

15 recordsLinked to original sources
PubMed2026

Comparing trajectories of cognitive functioning in treatment-resistant and non-resistant depression: a multicentre linear mixed-effects analysis.

BACKGROUND: Impaired cognitive functioning is a severe symptom in major depressive disorder (MDD). Recent evidence suggests it may be a central characteristic in its treatment resistant form (TRD), potentially constituting a clinical marker for treatment resistance and a target amenable to intervention. To date, cognitive functioning in TRD remains poorly understood and longitudinal investigations are scarce. METHODS: This observational prospective cohort study, including 320 patients diagnosed with MDD from the multicentre PROMPT study, examined differences in cognitive functioning between 118 TRD and 202 non-TRD patients over a period of twelve weeks in a real-world setting, using linear mixed modelling. Patients that failed to respond to at least two prior antidepressants trials at baseline were classified as TRD. RESULTS: TRD patients showed significantly poorer baseline performances than non-TRD patients in attention/processing speed (β = -0.45; 95%CI[-0.70, -0.19]; FDR-p = 0.003) and verbal memory (β = -0.45; 95%CI[-0.72, -0.18]; FDR-p = 0.003). Significant time × group interactions were observed in motor speed and verbal fluency tasks. Post-hoc-analyses revealed stagnation in TRD patients and significant improvement in non-TRD patients. Across all other tasks improvement was observed in both groups, and random effects showed large heterogeneity between patients, indicating notable individual differences in cognitive performances. CONCLUSIONS: The results suggest distinct recovery patters between non-TRD and TRD patients, and diminished functioning in TRD patients at the domain level. However, intact and diminished performances likely occur in both groups, warranting further investigation of cognitive heterogeneity. These short-term findings highlight the need for more comprehensive longitudinal research on cognition in TRD.

Humans↗
PubMed2004

Towards a MIP-based alignment and docking in computer-aided drug design.

Structural alignment of ligands in their biological conformation is a crucial step in the building of pharmacophoric models in structure-based drug design. In addition, docking algorithms are limited in some cases by the quality of the scoring functions and the limited flexibility of the environment that the different programs allow. On the other hand, GRID molecular interaction potentials (MIPs) have been used for a long time in 3D-QSAR studies. However, in most of these studies the alignment of the molecules is performed on the basis of geometrical or physico-chemical criteria that differ from the MIPs used in the partial least squares statistical analysis. We have previously developed a method to use the same scoring function for the molecular alignment and for 3D-QSAR studies. This methodology, based on the use of GRID potentials, consists in the weighted averaging of similarities of the relevant MIPs of the molecules to be aligned. Here we present a method to obtain the weights for the different GRID probes in the average based on the structural information on protein-ligand complexes for relevant systems. The method, implemented in MIPSIM, is shown to yield good accuracy in the prediction of the alignments for two systems: a set of three inhibitors of dihydrofolate reductase and a set of fifteen non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs). The smooth GRID potentials are shown to capture the flexible character of the active site, as opposed to traditional docking scoring energy functions.

Binding Sites↗
PubMed2004

Comparative analysis of putative agonist-binding modes in the human A1 adenosine receptor.

A recent study reported a model of the human A(1) adenosine receptor and its agonist binding site, proposing two putative binding modes in the same binding site for the natural agonist, adenosine. The present work investigates the flexibility of this binding site by exhaustive exploration with the natural agonist and with three other adenosine derivatives: N6-cyclopentyladenosine (CPA), 2-chloro-N6-cyclopentyladenosine (CCPA), and 5'-N-ethylcarboxamidoadenosine (NECA). Our aim was to find a common binding mode for agonists that would explain the role in the binding process of the different substitutions allowed at the 2, N6, and 5' positions of adenosine. This problem was addressed through docking simulations, molecular dynamics studies, and estimations of the ligand-binding free energy with both the AUTODOCK scoring function and the linear interaction energy (LIE) approach. The results point to a single receptor-binding position that explains the effects of the different chemical modifications on the adenosine derivatives considered here.

Adenosine↗
PubMed2004

Incorporating molecular shape into the alignment-free Grid-Independent Descriptors.

The recently introduced GRid-INdependent Descriptors (GRIND) were designed to provide a suitable description of a series of ligands for 3D-QSAR studies not requiring the spatial superimposition of their structures. Despite the proven usefulness of the method, it was recognized that the original GRIND failed to describe appropriately the shape of the ligand molecules, which in some cases plays a major role in ligand-receptor binding. For this reason, the original descriptors have been enhanced with the addition of a molecular shape description based on the local curvature of the molecular surface. The integration of this description into the GRIND allows the generation of 3D-QSAR models able to identify both favorable and unfavorable shape complementarity in a simple and alignment-independent way. The usefulness of the new GRIND-shape description in 3D-QSAR is illustrated using two structure-activity studies: one performed on a set of xanthine-like antagonists of the A(1) adenosine receptor; another performed on a series of Plasmodium falciparum plasmepsin II inhibitors.

Adenosine A1 Receptor Antagonists↗
PubMed2004

Novel approaches for modeling of the A1 adenosine receptor and its agonist binding site.

The present work describes the building of a human A(1) adenosine receptor (hA(1)AR) model, based on the X-ray crystal structure of bovine rhodopsin, and its use as a basis for the investigation of some important structural characteristics of the receptor. One of the issues investigated was the protonation position of two histidine residues known to influence ligand binding, with protonation of His251 (6.52) in epsilon position and His278 (7.43) in delta position showing the best agreement with experimental evidence. The model was also used to study the position and structural role of water molecules present in the helical bundle. Finally, the binding site location and the ligand docking were investigated using an objective strategy. A suitable site for the binding of the ribose moiety of adenosine was first postulated and further confirmed by means of a novel chemometric strategy based on GRIND descriptors. Using this position as an anchor point, the binding of adenosine was studied by docking and molecular dynamics simulations obtaining two putative binding positions in good agreement with experimental data.

Adenosine↗
PubMed2004

Continuing education and community pharmacists in Galicia: a study of opinions.

AIM OF THE STUDY: To determine the opinions of a volunteer group of community pharmacists concerning general and specific issues related to continuing education. METHODS: Participants were required to complete questionnaires before and after attendance at a refresher course, and score the relevant options provided on a scale from 0 to 10. The responses of the survey were analyzed to identify preferences and to detect any possible changes in opinion. MAIN OUTCOME MEASURE: Arithmetic means of pharmacists' opinions. RESULTS: The teaching methods preferred by the community pharmacists were workshops for resolution of practical cases (9 +/- 0.25 and 8.88 +/- 0.13) and the distance-learning computer programmes (6.74 +/- 0.25 and 8.18 +/- 0.20). In selecting which topics that should be taught, the participants gave the highest ratings to healthcare needs (8.75 +/- 0.14 and 8.57 +/- 0.15) and the demands of the pharmacists (8.15 +/- 0.16 and 8.40 +/- 0.16), with pharmaceutical care being the most requested topic (29 points). Participants preferred courses lasting 20 to 50 hours (6.94 +/- 0.26 and 7.89 +/- 0.16), without preference for schedule. CONCLUSION: Community pharmacists in Galicia show a great interest in the provision and organization of continuing education activities that meet their needs and expectations.

Adult↗
PubMed2004

[Computer-assisted clinical decision support systems].

This review deals with the historical evolution and methodological basis of computerized medical decision support tools. It also reviews the verification, validation and impact evaluation methods of these systems. The acceptability of them from the health professionals depends on the pro-activity and usefulness of the systems, between other factors. The clinical impact evaluation methods are described in deep detail and the Hunt et al review of 1998 is updated.

Decision Making, Computer-Assisted↗
PubMed2004

Structuring European biomedical informatics to support individualized healthcare: current issues and future trends.

Bioinformatics and Medical Informatics are disciplines that up to now have followed separate development with few contacts and synergies between them in Europe. The elucidation of the human genome has however evidenced the need and the possibilities for a strong synergy between the two. Classical epidemiological and clinical research on the one hand, and genomic research on the other, separately considered, are no longer enough for advancing in the so-called genomic medicine, and a new integrative approach is required. Biomedical Informatics is the emerging discipline that aims to put these two worlds together so that the discovery and creation of novel diagnostic and therapeutic methods is fostered. On the basis of the results of the European Commission-funded BIOINFOMED Study, an INFOBIOMED Network of Excellence has been recently constituted with the main objective of setting a durable structure for the described collaborative approach at a European level. Initially formed by fifteen renowned European organisations, the main objective of the INFOBIOMED network is therefore to enable the reinforcement of European BMI as an integrative discipline.

Biomedical Research↗
PubMed2003

On the generation of catalytic antibodies by transition state analogues.

The effective design of catalytic antibodies represents a major conceptual and practical challenge. It is implicitly assumed that a proper transition state analogue (TSA) can elicit a catalytic antibody (CA) that will catalyze the given reaction in a similar way to an enzyme that would evolve (or was evolved) to catalyze this reaction. However, in most cases it was found that the TSA used produced CAs with relatively low rate enhancement as compared to the corresponding enzymes, when these exist. The present work explores the origin of this problem, by developing two approaches that examine the similarity of the TSA and the corresponding transition state (TS). These analyses are used to assess the proficiency of the CA generated by the given TSA. Both approaches focus on electrostatic effects that have been found to play a major role in enzymatic reactions. The first method uses molecular interaction potentials to look for the similarity between the TSA and the TS and, in principle, to help in designing new haptens by using 3D quantitative structure-activity relationships. The second and more quantitative approach generates a grid of Langevin dipoles, which are polarized by the TSA, and then uses the grid to bind the TS. Comparison of the resulting binding energy with the binding energy of the TS to the grid that was polarized by the TS provides an estimate of the proficiency of the given CA. Our methods are used in examining the origin of the difference between the catalytic power of the 1F7 CA and chorismate mutase. It is demonstrated that the relatively small changes in charge and structure between the TS and TSA are sufficient to account for the difference in proficiency between the CA and the enzyme. Apparently the environment that was preorganized to stabilize the TSA charge distribution does not provide a sufficient stabilization to the TS. The general implications of our findings and the difficulties in designing a perfect TSA are discussed. Finally, the possible use of our approach in screening for an optimal TSA is pointed out.

Antibodies, Catalytic↗
PubMed2003

Conformationally constrained butyrophenones as new pharmacological tools to study 5-HT 2A and 5-HT 2C receptor behaviours.

This study presents new pharmacological and molecular modelling studies on a recently described series of conformationally constrained butyrophenones. Alignment-free three-dimensional quantitative structure-activity relationship models developed on the basis of GRid Independent descriptors and partial least squares regression analysis, allow feasible predictions of activity of new compounds and reveal structural requirements for optimal affinity, particularly in the case of the 5-HT(2A) receptor. The requirements for the 5-HT(2A) affinity consist in a precise distance between hydrogen bond donor (protonated amino group) and hydrogen bond acceptor groups, as well as an optimal distance between the protonated amino group and the farthest extreme of the compounds. Another significant result has been the characterisation of two structurally similar compounds as interesting pharmacological tools (1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine and 1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine). In spite of their structural similarity, the first compound shows clearly higher affinity for the 5-HT(2C) receptor (about 100 fold) and higher Meltzer ratio (1.17 vs. 0.99) than the second. Moreover, the first compound inhibits arachidonic acid release in a biphasic concentration-dependent way in functional experiments at the 5-HT(2A) receptor and it acts as inverse agonist at the 5-HT(2C) receptor, behaviours that are not shown by the second compound.

Animals↗
PubMed2003

Use of alignment-free molecular descriptors in diversity analysis and optimal sampling of molecular libraries.

The selection of a sample of diverse compounds is a common strategy for exploring large molecular libraries. However, the success of such approach depends on the selection of relevant molecular descriptors and the use of appropriate sampling methods. In the context of pharmaceutical research, the molecular descriptors should be based on physicochemical properties related with the pharmacological behaviour of the compounds. In this sense, the alignment-free GRIND and VolSurf molecular descriptors are promising candidates since they have been successfully used in the modelling of both pharmacodynamic and pharmacokinetic properties of drugs. This work describes the use of such descriptors in the diversity sampling of a library of primary amines and compares the results with those obtained in a previous study that used quantum-mechanical descriptors. As in the previous work, principal component (PC) analysis was applied to reduce the dimensionality and remove redundant information of the original descriptors, and the compounds were sampled on the basis of k-means clustering on the space of the selected PCs. The results of the present study show that VolSurf and GRIND provide similar quality sampling regarding global features of the molecules such as hydrophilicity, however the topology of the compounds is considered differently. The similarity between particular compounds strongly depends on the original descriptors used. However all the sample selections done in the PC space after k-means clustering provide the same apparent diversity in comparison to the whole dataset. The results indicate that there is no best set of descriptors on a diversity basis. The selection of descriptors must be based on the drug features to be investigated.

Combinatorial Chemistry Techniques↗
PubMed2002

New serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptor antagonists: synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo and heterocycloalkanones.

A series of 52 conformationally constrained butyrophenones have been synthesized and pharmacologically tested as antagonists at 5-HT(2A), 5-HT(2B), and 5-HT(2C) serotonin receptors, useful for dissecting the role of each 5-HT(2) subtype in pathophysiology. These compounds were also a consistent set for the identification of structural features relevant to receptor recognition and subtype discrimination. Six compounds were found highly active (pK(i) > 8.76) and selective at the 5-HT(2A) receptor vs 5-HT(2B) and/or 5-HT(2C) receptors. Piperidine fragments confer high affinity at the 5-HT(2A) receptor subtype, with benzofuranone- and thiotetralonepiperidine as the most selective derivatives over 5-HT(2C) and 5-HT(2B) receptors, respectively; K(i) (2A/2C) and/or K(B) (2A/2B) ratios greater than 100 were obtained. Compounds showing a more pronounced selectivity at 5-HT(2A)/5-HT(2C) than at 5-HT(2A)/5-HT(2B) bear 6-fluorobenzisoxazolyl- and p-fluorobenzoylpiperidine moieties containing one methylene bridging the basic piperidine to the alkanone moiety. An ethylene bridge between the alkanone and the amino moieties led to ligands with higher affinities for the 5-HT(2B) receptor. Significant selectivity at the 5-HT(2B) receptor vs 5-HT(2C) was observed with 1-1[(1-oxo-1,2,3,4-tetrahydro-3-naphthyl)methyl]-4-[3-(p-fluorobenzoyl)propyl]piperazine (more than 100-fold higher). Although piperidine fragments also confer higher affinity at 5-HT(2C) receptors, only piperazine-containing ligands were selective over 5-HT(2A). Moderate selectivity was observed at 5-HT(2C) vs 5-HT(2B) (10-fold) with some compounds bearing a 4-[3-(6-fluorobenzisoxazolyl)]piperidine moiety in its structure. Molecular determinants for antagonists acting at 5-HT(2A) receptors were identified by 3D-QSAR (GRID-GOLPE) studies. Docking simulations at 5-HT(2A) and 5-HT(2C) receptors suggest a binding site for the studied type of antagonists (between transmembrane helices 2, 3, and 7) different to that of the natural agonist serotonin (between 3, 5, and 6).

Animals↗
PubMed2002

Distant collaboration in drug discovery: the LINK3D project.

The work describes the development of novel software supporting synchronous distant collaboration between scientists involved in drug discovery and development projects. The program allows to visualize and share data as well as to interact in real time using standard intranets and Internet resources. Direct visualization of 2D and 3D molecular structures is supported and original tools for facilitating remote discussion have been integrated. The software is multiplatform (MS-Windows, SGI-IRIX, Linux), allowing for a seamless integration of heterogeneous working environments. The project aims to support collaboration both within and between academic and industrial institutions. Since confidentiality is very important in some scenarios, special attention has been paid to security aspects. The article presents the research carried out to gather the requirements of collaborative software in the field of drug discovery and development and describes the features of the first fully functional prototype obtained. Real-world testing activities carried out on this prototype in order to guarantee its adequacy in diverse environments are also described and discussed.

Computer Graphics↗
PubMed2002

Influence of pH on the binding of diphenylmethylenepiperidines by 5-HT2B receptors in rat stomach fundus.

Cyproheptadine is one of the compounds exhibiting the highest activity at 5-HT2B receptors. In a previous work we analysed the relevance of the amino group in diphenylmethylenepiperidines (DPMP), which are open cyproheptadine analogues. Only compounds containing N-H or N-methyl motifs, showed significant 5-HT2B activity. Surprisingly, the corresponding quaternary ammonium salt demonstrated a total lack of activity. Therefore, the question arises whether protonation favours the interaction of these compounds with 5-HT2B receptors. Consequently, we studied the protonation influence (by varying the pH of the medium) on the antagonism of serotonin by some cyproheptadine analogues in rat stomach fundus. The main results were: 1) N-protonation increases the activity of DPMPs. 2) Alkaline pH facilitates the occurrence of a non-surmountable antagonism. 3) The contrast between the activity of protonated DPMPs and the lack of activity of the corresponding quaternary ammonium cation, suggests either that the latter is prevented from acting by steric hindrance, or that the mechanism by which protonation may increase the activity depends not only on the charge of the proton, but also on its ability to form hydrogen bonds.

Animals↗