Setting up a large set of protein-ligand PDB complexes for the development and validation of knowledge-based docking algorithms

<p>Abstract</p> <p>Background</p> <p>The number of algorithms available to predict ligand-protein interactions is large and ever-increasing. The number of test cases used to validate these methods is usually small and problem dependent. Recently, several databases have been released for further understanding of protein-ligand interactions, having the Protein Data Bank as backend support. Nevertheless, it appears to be difficult to test docking methods on a large variety of complexes. In this paper we report the development of a new database of protein-ligand complexes tailored for testing of docking algorithms.</p> <p>Methods</p> <p>Using a new definition of molecular contact, small ligands contained in the 2005 PDB edition were identified and processed. The database was enriched in molecular properties. In particular, an automated typing of ligand atoms was performed. A filtering procedure was applied to select a non-redundant dataset of complexes. Data mining was performed to obtain information on the frequencies of different types of atomic contacts. Docking simulations were run with the program DOCK.</p> <p>Results</p> <p>We compiled a large database of small ligand-protein complexes, enriched with different calculated properties, that currently contains more than 6000 non-redundant structures. As an example to demonstrate the value of the new database, we derived a new set of chemical matching rules to be used in the context of the program DOCK, based on contact frequencies between ligand atoms and points representing the protein surface, and proved their enhanced efficiency with respect to the default set of rules included in that program.</p> <p>Conclusion</p> <p>The new database constitutes a valuable resource for the development of knowledge-based docking algorithms and for testing docking programs on large sets of protein-ligand complexes. The new chemical matching rules proposed in this work significantly increase the success rate in DOCKing simulations. The database developed in this work is available at <url>http://cimlcsext.cim.sld.cu:8080/screeningbrowser/</url>.</p

Discovery of os cordis in the cardiac skeleton of chimpanzees (Pan troglodytes)

Cardiovascular diseases, especially idiopathic myocardial fibrosis, is one of the most significant causes of morbidity and mortality in captive great apes. This study compared the structure and morphology of 16 hearts from chimpanzees (Pan troglodytes) which were either healthy or affected by myocardial fibrosis using X-ray microtomography. In four hearts, a single, hyperdense structure was detected within the right fibrous trigone of the cardiac skeleton. High resolution scans and histopathology revealed trabecular bones in two cases, hyaline cartilage in another case and a focus of mineralised fibro-cartilaginous metaplasia with endochondral ossification in the last case. Four other animals presented with multiple foci of ectopic calcification within the walls of the great vessels. All hearts affected by marked myocardial fibrosis presented with bone or cartilage formation, and increased collagen levels in tissues adjacent to the bone/cartilage, while unaffected hearts did not present with os cordis or cartilago cordis. The presence of an os cordis has been described in some ruminants, camelids, and otters, but never in great apes. This novel research indicates that an os cordis and cartilago cordis is present in some chimpanzees, particularly those affected by myocardial fibrosis, and could influence the risk of cardiac arrhythmias and sudden death

Small-animal SPECT and SPECT/CT: application in cardiovascular research

Preclinical cardiovascular research using noninvasive radionuclide and hybrid imaging systems has been extensively developed in recent years. Single photon emission computed tomography (SPECT) is based on the molecular tracer principle and is an established tool in noninvasive imaging. SPECT uses gamma cameras and collimators to form projection data that are used to estimate (dynamic) 3-D tracer distributions in vivo. Recent developments in multipinhole collimation and advanced image reconstruction have led to sub-millimetre and sub-half-millimetre resolution SPECT in rats and mice, respectively. In this article we review applications of microSPECT in cardiovascular research in which information about the function and pathology of the myocardium, vessels and neurons is obtained. We give examples on how diagnostic tracers, new therapeutic interventions, pre- and postcardiovascular event prognosis, and functional and pathophysiological heart conditions can be explored by microSPECT, using small-animal models of cardiovascular disease

Apelin Attenuates the Osteoblastic Differentiation of Vascular Smooth Muscle Cells

Vascular calcification, which results from a process osteoblastic differentiation of vascular smooth muscle cells (VSMCs), is a major risk factor for cardiovascular morbidity and mortality. Apelin is a recently discovered peptide that is the endogenous ligand for the orphan G-protein-coupled receptor, APJ. Several studies have identified the protective effects of apelin on the cardiovascular system. However, the effects and mechanisms of apelin on the osteoblastic differentiation of VSMCs have not been elucidated. Using a culture of calcifying vascular smooth muscle cells (CVMSCs) as a model for the study of vascular calcification, the relationship between apelin and the osteoblastic differentiation of VSMCs and the signal pathway involved were investigated. Alkaline phosphatase (ALP) activity and osteocalcin secretion were examined in CVSMCs. The involved signal pathway was studied using the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002, and APJ siRNA. The results showed that apelin inhibited ALP activity, osteocalcin secretion, and the formation of mineralized nodules. APJ protein was detected in CVSMCs, and apelin activated ERK and AKT (a downstream effector of PI3-K). Suppression of APJ with siRNA abolished the apelin-induced activation of ERK and Akt. Furthermore, inhibition of APJ expression, and the activation of ERK or PI3-K, reversed the effects of apelin on ALP activity. These results showed that apelin inhibited the osteoblastic differentiation of CVSMCs through the APJ/ERK and APJ/PI3-K/AKT signaling pathway. Apelin appears to play a protective role against arterial calcification

Vitamina D y parathormona en gestantes en último trimestre y en sangre del cordón umbilical

Introducción: La vitamina D (VD) es un micronutriente y prohormona involucrada en el metabolismo calcio/fósforo, crecimiento somático y diferenciación celular. Su déficit en el embarazo afecta al binomio madre-niño; esto ha sido reportado en varios países, pero es necesaria mayor documentación de acuerdo con circunstancias particulares. Objetivos: Evaluar el comportamiento de la VD durante el tercer trimestre de gestación y en el cordón umbilical (CU), y establecer la relación con factores asociados y variables bioquímicas. Métodos: Investigación descriptiva y correlacional. Durante el periodo octubre 2015 a septiembre 2016 se evaluaron 346 binomios madre-niño atendidos en el Hospital de Tomelloso, Ciudad Real, España. Datos: edad materna y gestacional, tipo de parto, ingesta de polivitamínicos, etnia, fenotipo cutáneo, ropa usada, antropometría, sexo y Apgar del neonato. Evaluación de variables bioquímicas maternas y en sangre de CU post-pinzamiento. Déficit de VD: valores &lt; 20ng/ml. Se evaluó ingesta de calcio y VD materna y exposición solar. Se describe estadística descriptiva y no paramétrica y las correlaciones entre variables y comparación entre grupos. Resultados: Gestantes: 72% déficit grave o moderado. CU: 61% de deficiencia, con tendencia a déficit grave en invierno. Significancia entre niveles de VD y tipo de ropa, rango mayor en mujeres que usan ropa que no cubre cabeza, cuello y manos. Gestantes Gitanas y Marroquíes presentaron valores menores. Hubo correlación entre VD materna con exposición solar, niveles de parathormona y VD en CU. Conclusiones: Se encontró deficiencia de VD materna y en CU, lo cual sugiere necesidad terapéutica desde la gestación temprana. Introduction: Vitamin D (VD), is a micronutrient and prohormone involved in calcium/phosphorus metabolism, somatic growth and cellular differentiation. Its deficit in pregnancy could affect the mother-child binomial; this has been reported in several countries, but additional documentation is necessary according to circumstances. Objectives: To evaluate VD levels during the third trimester of gestation and in umbilical cord blood (UC), and also the relationship with associated factors and biochemical variables. Methods: Descriptive and correlational investigation. During the period from october 2015 to september 2016, 346 mother-newborn binomials were evaluated at Hospital of Tomelloso, Ciudad Real, Spain. Data: maternal and gestational age, type of delivery, intake of polyvitamins, ethnicity, skin phenotype, used clothing, anthropometric measurement and sex of the newborn and Apgar. maternal biochemical variables and post-clamping UC blood sample were evaluated. VD deficit: values &lt; 20ng/ml. calcium intake and maternal VD and solar exposition were evaluated. Descriptive and nonparametric statistic, correlations between variables and comparison between groups. Results: Pregnant mothers: 72% had severe or moderate deficit. CU: 61% deficiency, with a tendency to severe deficit in winter. Significant correlation was obtained between VD levels and clothing type, higher values in women who wear clothes with no head, neck or hands coverage. Gypsy and Moroccans mothers had lower values. Correlation between maternal VD with sun exposure, parathormone levels and VD in UC was found. Conclusions: Deficiency of maternal VD and in UC was detected, suggesting that therapeutic intervention is needed from earlypregnancy to maintain the health of the binomial

Examples of molecules that were correctly protonated by the modified Babel program

<p><b>Copyright information:</b></p><p>Taken from "Setting up a large set of protein-ligand PDB complexes for the development and validation of knowledge-based docking algorithms"</p><p>http://www.biomedcentral.com/1471-2105/8/310</p><p>BMC Bioinformatics 2007;8():310-310.</p><p>Published online 25 Aug 2007</p><p>PMCID:PMC2008766.</p><p></p> A) Biotin. The atom C2 was correctly typed as sp3, and then a hydrogen was added to fill the empty valence; B) Moxiraprine. The hydrogen atoms marked with red X's were removed by applying an empirical rule that allows correct protonation of this type of ring

Results from the docking simulations performed for 542 complexes from the PDB2005 dataset, using three different sets of chemical matching rules

<p><b>Copyright information:</b></p><p>Taken from "Setting up a large set of protein-ligand PDB complexes for the development and validation of knowledge-based docking algorithms"</p><p>http://www.biomedcentral.com/1471-2105/8/310</p><p>BMC Bioinformatics 2007;8():310-310.</p><p>Published online 25 Aug 2007</p><p>PMCID:PMC2008766.</p><p></p> Panels A, B and C show the distribution of RMSD values of the best found solution using the native DOCK, R1 and R2 sets of matching rules, respectively. Panels D, E and F show the distribution of the total number of orientations (N) explored in the simulations, for the same sets of matching rules

Distribution of probable (F) and very probable (VF) protein-ligand complexes, given in percent relative to the number of matching pairs

<p><b>Copyright information:</b></p><p>Taken from "Setting up a large set of protein-ligand PDB complexes for the development and validation of knowledge-based docking algorithms"</p><p>http://www.biomedcentral.com/1471-2105/8/310</p><p>BMC Bioinformatics 2007;8():310-310.</p><p>Published online 25 Aug 2007</p><p>PMCID:PMC2008766.</p><p></p> A cut-off matching distance of 1.5 Å was used to compute the ligand atom-attached point matching pairs