Protein Functional Families to characterise drug-target interactions.

The quest for “magic bullets” has been the driving force in drug discovery during the last two decades. However, the increasing rate of drug failure over this period has occurred concurrently with the assumption that a drug is a selective ligand for a single target. It now seems likely that polypharmacology is the rule rather than the exception [1]. Our previous research shows that protein domains are a good proxy for drug targets, and that drug polypharmacology emerges as a consequence of the multi-domain composition of proteins [2]. In this study, we investigate further the idea that the domain is the druggable entity within a protein target. We have identified a specific class of domains (CATH Functional Families) as the best currently available for identifying drug-target interactions. We show how this opens a new direction in target identification with potential application in drug repurposing.1. Hopkins, AL. (2008) Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol; 4: 682 2. Moya-García AA & Ranea JAG (2013) Insights into polypharmacology from drug-domain associations. Bioinformatics 29: 1934–1937)Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. Universidad de Granad

Network perspective of histamine related diseases

Histamine is the most pleiotropic biogenic amine. Produced and stored by a limited set of cells—histaminergic neurons, enterochromaffin-like cells, and mast cells—it broadcasts intercellular communication signals to a wide variety of cell types through its tissue-specific receptors. The many molecular interactions of these receptors and other mediators result in complex cellular networks whose alteration result in disease. Therefore, complex diseases map to modules of these cellular networks in the diseasomes. In this communication, we survey the histamine cellular networks to map the histamine diseasome, presenting a network view of the pleiotropy of histamine and its role in several complex diseases.A.A. Moya is a CIBERER fellow. The "CIBER de Enfermedades Raras" is an initiative from the ISCIII (Spain)]. This communication has the support of a travel grant "Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech"

Exploiting protein family and protein network data to identify novel drug targets for bladder cancer

Bladder cancer remains one of the most common forms of cancer and yet there are limited small molecule targeted therapies. Here, we present a computational platform to identify new potential targets for bladder cancer therapy. Our method initially exploited a set of known driver genes for bladder cancer combined with predicted bladder cancer genes from mutationally enriched protein domain families. We enriched this initial set of genes using protein network data to identify a comprehensive set of 323 putative bladder cancer targets. Pathway and cancer hallmarks analyses highlighted putative mechanisms in agreement with those previously reported for this cancer and revealed protein network modules highly enriched in potential drivers likely to be good targets for targeted therapies. 21 of our potential drug targets are targeted by FDA approved drugs for other diseases - some of them are known drivers or are already being targeted for bladder cancer (FGFR3, ERBB3, HDAC3, EGFR). A further 4 potential drug targets were identified by inheriting drug mappings across our in-house CATH domain functional families (FunFams). Our FunFam data also allowed us to identify drug targets in families that are less prone to side effects i.e., where structurally similar protein domain relatives are less dispersed across the human protein network. We provide information on our novel potential cancer driver genes, together with information on pathways, network modules and hallmarks associated with the predicted and known bladder cancer drivers and we highlight those drivers we predict to be likely drug targets

El grau de satisfacció dels usuaris i la seva relació amb la qualitat del servei, al programa de senderisme de la Diputació de Granada. Anàlisi i estudi dels diferents programes de senderisme a la província de Granada

Els gestors esportius han de garantir l’eficiència i l’eficàcia dels recursos públics assignats als serveis esportius, basant-se en estudis sistemàtics, que impedeixin de deixar coses a l’atzar. De la mateixa manera, les polítiques socials, que permeten aquests serveis, han de garantir la satisfacció de necessitats socials reals i ajustades a cada realitat en particular. Realitat que es viu diferent entre la població d’una Entitat Local, i encara més entre poblacions de diferents Entitats Locals. Per això, el tipus d’informació que cal aplegar és qualitatiu, atès que s’han de conèixer els sentiments, opinions, motius, necessitats, expectatives, desigs per practicar un tipus d’activitat física i/o esport. Caldrà conèixer les eines, els mitjans necessaris per aconseguir aquesta informació. Això permetrà d’assignar recursos i esforços a millorar les característiques a les quals hom atribueix més importància i eliminar els esforços en les valorades com a no importants i que no estan donant satisfacció als senderistes. L’estudi se centra en l’anàlisi de l’oferta pública de 12 Entitats Locals Granadines que ofereixen el servei esportiu de senderisme en la temporada 2002-2003. Es va estudiar, entre d’altres coses, la valoració de qualitat de cada un, i també la satisfacció que reportava als senderistes. Els tres qüestionaris utilitzats van ser els següents: Qüestionari 1. Per estudiar la banda de tolerància de les dimensions de qualitat de cada programa de senderisme per als seus usuaris. Creat i validat en el procés d’investigació. Els instruments que es van utilitzar van ser l’entrevista telefònica i el qüestionari autogestionat per realitzar l’observació sociològica. Per delimitar-ne la llista de dimen­sions de qualitat, es va utilitzar el mètode de l’incident crític. Aquest mètode es basa a identificar sota aquesta terminologia les descripcions, tant positives com negatives, que el client fa sobre el servei. Qüestionari 2. Per conèixer el perfil del senderista granadí. Aquest qüestionari es va desenvolupar a través de preguntes sociodemogràfiques i psicogràfiques. A més a més, es van formular preguntes per conèixer el judici de satisfacció i qualitat global, i preguntes per conèixer la fidelitat del senderista al programa de senderisme que realitzava. Qüestionari 3. Anomenat MODE, per estudiar les motiva­cions esportives que porten el senderista a realitzar l’esport

A course-based undergraduate research experience to illustrate the early stages of the drug discovery process

We have implemented at the University of Málaga (Spain) a new course-based undergraduate research experience (CURE) to involve undergraduate students of Science in a real-world scientific problem. Within the topic “Let's find acetylcholinesterase inhibitors as new drug candidates for the treatment of Alzheimer's”, students have been engaged into the early stages of the drug discovery process. Working in groups of 4–5 persons, they have searched information in databases, proposed solutions to the driving question and designed protocols to carry them out in vitro and in silico. Overall, the implementation of this experience has been very satisfactory in terms of academic performance and students' perception. This article reports a session from the virtual international 2021 IUBMB/ASBMB workshop, “Teaching Science on Big Data”.This work was supported by the University of Málaga (Spain) funds granted to the educational innovation projects PIE19-086. Open access funded by Universidad de Málaga/CBUA

KinFams: De-Novo Classification of Protein Kinases Using CATH Functional Units

Protein kinases are important targets for treating human disorders, and they are the second most targeted families after G-protein coupled receptors. Several resources provide classification of kinases into evolutionary families (based on sequence homology); however, very few systematically classify functional families (FunFams) comprising evolutionary relatives that share similar functional properties. We have developed the FunFam-MARC (Multidomain ARchitecture-based Clustering) protocol, which uses multi-domain architectures of protein kinases and specificity-determining residues for functional family classification. FunFam-MARC predicts 2210 kinase functional families (KinFams), which have increased functional coherence, in terms of EC annotations, compared to the widely used KinBase classification. Our protocol provides a comprehensive classification for kinase sequences from >10,000 organisms. We associate human KinFams with diseases and drugs and identify 28 druggable human KinFams, i.e., enriched in clinically approved drugs. Since relatives in the same druggable KinFam tend to be structurally conserved, including the drug-binding site, these KinFams may be valuable for shortlisting therapeutic targets. Information on the human KinFams and associated 3D structures from AlphaFold2 are provided via our CATH FTP website and Zenodo. This gives the domain structure representative of each KinFam together with information on any drug compounds available. For 32% of the KinFams, we provide information on highly conserved residue sites that may be associated with specificity.Adeyelu T, Bordin N, Waman VP, Sadlej M, Sillitoe I, Moya-Garcia AA, Orengo CA. KinFams: De-Novo Classification of Protein Kinases Using CATH Functional Units. Biomolecules. 2023; 13(2):277. https://doi.org/10.3390/biom1302027

Genes involved in immune reinduction may constitute biomarkers of response for metastatic melanoma patients treated with targeted therapy

Targeted therapy in metastatic melanoma often achieves a major tumour regression response and significant long-term survival via the release of antigens that reinduce immunocompetence. The biomarkers thus activated may guide the prediction of response, but this association and its mechanism have yet to be established. Blood samples were collected from nineteen consecutive patients with metastatic melanoma before, during, and after treatment with targeted therapy. Differential gene expression analysis was performed, which identified the genes involved in the treatment, both in the first evaluation of response and during progression. Although clinical characteristics of the patients were poorer than those obtained in pivotal studies, radiological responses were similar to those reported previously (objective response rate: 73.7%). In the first tumour assessment, the expression of some genes increased (CXCL-10, SERPING1, PDL1, and PDL2), while that of others decreased (ARG1, IL18R1, IL18RAP, IL1R1, ILR2, FLT3, SLC11A1, CD163, and S100A12). The analysis of gene expression in blood shows that some are activated and others inhibited by targeted therapy. This response pattern may provide biomarkers of the immune reinduction response, which could be used to study potential combination treatments. Nevertheless, further studies are needed to validate these results.Fundación Progreso y Salud, Junta de Andalucí

AMMO-Prot: amine system project 3D-model finder

BACKGROUND: Amines are biogenic amino acid derivatives, which play pleiotropic and very important yet complex roles in animal physiology. For many other relevant biomolecules, biochemical and molecular data are being accumulated, which need to be integrated in order to be effective in the advance of biological knowledge in the field. For this purpose, a multidisciplinary group has started an ontology-based system named the Amine System Project (ASP) for which amine-related information is the validation bench. RESULTS: In this paper, we describe the Ontology-Based Mediator developed in the Amine System Project (http://asp.uma.es) using the infrastructure of Semantic Directories, and how this system has been used to solve a case related to amine metabolism-related protein structures. CONCLUSIONS: This infrastructure is used to publish and manage not only ontologies and their relationships, but also metadata relating to the resources committed with the ontologies. The system developed is available at http://asp.uma.es/WebMediator

Analisys of the fracture thoughness in the heat affected zone (HAZ) of one HSLA steel

Con la aportación original del trabajo experimental de investigación aquí realizado, se pretende asegurar que la tenacidad a la fractura KIC en la zona afectada por el calor (ZAC) del acero USITEN 355 0,5 Ni grado I, produce un CTOD (?) (Crack Tip Opening Displacement) con valores dentro de la norma, haciendo compatible el acero con el procedimiento de soldadura utilizado y la energía calorífica aportada de 2 kJ /mm, comprobando que el mecanismo de frenado del tamaño de grano llevado a cabo por los microaleantes (V, Nb, Al) del metal base funcionan conforme lo previsto. Además, se intenta asegurar, en la medida de lo posible, una correlación entre los parámetros de soldadura y los resultados obtenidos en los ensayos de fractura, de tal forma que, si los resultados obtenidos en los ensayos no fueran satisfactorios, se pudiese aplicar la solución adecuada en el soldeo para que los parámetros que regulan los ensayos de fractura sean aceptables. El trabajo aquí desarrollado es útil como guía y referencia para futuros trabajos de investigación de mecánica de la fractura en aceros microaleados