Clustering Molecular Dynamics Trajectories for Optimizing Docking Experiments

Molecular dynamics simulations of protein receptors have become an attractive tool for rational drug discovery. However, the high computational cost of employing molecular dynamics trajectories in virtual screening of large repositories threats the feasibility of this task. Computational intelligence techniques have been applied in this context, with the ultimate goal of reducing the overall computational cost so the task can become feasible. Particularly, clustering algorithms have been widely used as a means to reduce the dimensionality of molecular dynamics trajectories. In this paper, we develop a novel methodology for clustering entire trajectories using structural features from the substrate-binding cavity of the receptor in order to optimize docking experiments on a cloud-based environment. The resulting partition was selected based on three clustering validity criteria, and it was further validated by analyzing the interactions between 20 ligands and a fully flexible receptor (FFR) model containing a 20 ns molecular dynamics simulation trajectory. Our proposed methodology shows that taking into account features of the substrate-binding cavity as input for the k-means algorithm is a promising technique for accurately selecting ensembles of representative structures tailored to a specific ligand

Plan de negocios para la implementaci?n de la unidad de turismo m?dico del grupo San Pablo

Los Estados Unidos debido a su sistema de salud tiene los costos m?s altos a nivel mundial que limita la cobertura de los seguros; en este contexto, el turismo m?dico, que es el sector encargado de atender pacientes que viajan a un lugar diferente de su pa?s de origen para recibir un tratamiento espec?fico, se presenta como una opci?n viable e interesante, ya que permite a personas de recursos medios acceder a tratamientos a precios m?s c?modos y de igual calidad que sus pa?ses de origen. La idea del negocio consiste en la creaci?n de la unidad de turismo m?dico para el Grupo San Pablo con una oficina instalada en la ciudad de Miami que se encargar? de la promoci?n, captaci?n y venta de los paquetes tur?stico-m?dicos; posteriormente, el personal en Lima atender? la demanda est?tica de salud a un precio bastante menor y ofreciendo adem?s la gran experiencia del turismo en el Per?. La ventaja competitiva planteada es la atenci?n integral, humanizada, de calidad y centrada en el paciente; unida, a la gran experiencia de conocer el Per?, que posee un enorme potencial tur?stico aun no bien aprovechado

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A Many-analysts Approach to the Relation Between Religiosity and Well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β = 0.120). For the second research question, this was the case for 65% of the teams (median reported β = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Substrate-binding cavity of the InhA enzyme (PDB ID: 1BVR) identified by the CASTp software tool.

<p>On the left, the substrate-binding cavity of the 1BVR structure represented by molecular surface and colored by atom types (carbon and hydrogen: light grey; nitrogen: blue; oxygen: red; sulphur: yellow). The projection displays all residues from the binding pocket in stick representation.</p

3D structure of the 20 ligands used in docking experiments.

<p>Each ligand is colored by atom type (carbon and hydrogen: light grey; nitrogen: blue; oxygen: red; chloro: green; phosphorus: orange; sulphur: yellow) and displays its name and PDB identification (PDB ID). The dashed circle represents the rotatable bounds selected by AutoDockTools 1.5.6. Ligand Abbreviations: <b>TCL</b>: triclosan; <b>665:</b>(3S) N-(3-bromophenyl)-1-cyclohexyl-5-oxopyrrolidine- 3-carboxamide; <b>566:</b>(3S)-1-cyclohexyl-5-oxo-N-phenyl pyrrolidine-3-carboxamide; <b>8PC:</b> 2-(2,4-dichloro-phenoxy)-5-(pyridin-2-ylmethyl)phenol; <b>JPJ:</b> 2-(2,4-dichlorophenoxy)-5-(2-phenylethyl)phenol; <b>JPL:</b> 5-(cyclohexa-1,5-dien-1-ylmethyl)-2-(2,4-dichlorophenoxy) phenol; <b>JPM:</b> 5-benzyl-2-(2,4-dichloropheno-xy)phenol; <b>468:</b>(3S)-N-(3-chloro-2-methylphenyl)-1-cyclohe xyl-5-oxopyrrolidine-3-carboxamide; <b>641:</b>(3S)-1-cyclohexyl-N-(3,5-dichlorophenyl)-5-oxopyrrolidine-3-carboxamide; <b>744:</b> (3S)-N-(5-chloro-2-me-thylphenyl)-1-cyclohexyl-5-oxopyrrolidine-3-carboxamide; <b>INH-NAD:</b> Isoniazid + NADH coenzyme; <b>5PP:</b> 5-pentyl-2-phenoxyphenol; <b>8PS:</b> 5-octyl-2-phenoxyphenol; <b>TCU:</b> 5-hexyl-2-(2-methylphenoxy)- phenol; <b>PTH-NAD:</b> Prothionamide + NADH coenzyme; <b>THT:</b> trans-2-hexadecenoyl-(n-acetyl-cys-teamine)- thioester <b>4PI:</b> N-4-methylbenzoyl-4-benzylpiperidine; <b>GEQ:</b> 5-{[4-9H-fluoren-9-YL)pipera- zin-1-YL]carbonyl}-1H-indole.</p

An Effective Approach for Clustering InhA Molecular Dynamics Trajectory Using Substrate-Binding Cavity Features

<div><p>Protein receptor conformations, obtained from molecular dynamics (MD) simulations, have become a promising treatment of its explicit flexibility in molecular docking experiments applied to drug discovery and development. However, incorporating the entire ensemble of MD conformations in docking experiments to screen large candidate compound libraries is currently an unfeasible task. Clustering algorithms have been widely used as a means to reduce such ensembles to a manageable size. Most studies investigate different algorithms using pairwise Root-Mean Square Deviation (RMSD) values for all, or part of the MD conformations. Nevertheless, the RMSD only may not be the most appropriate gauge to cluster conformations when the target receptor has a plastic active site, since they are influenced by changes that occur on other parts of the structure. Hence, we have applied two partitioning methods (<i>k</i>-means and <i>k</i>-medoids) and four agglomerative hierarchical methods (Complete linkage, Ward’s, Unweighted Pair Group Method and Weighted Pair Group Method) to analyze and compare the quality of partitions between a data set composed of properties from an enzyme receptor substrate-binding cavity and two data sets created using different RMSD approaches. Ensembles of representative MD conformations were generated by selecting a medoid of each group from all partitions analyzed. We investigated the performance of our new method for evaluating binding conformation of drug candidates to the InhA enzyme, which were performed by cross-docking experiments between a 20 ns MD trajectory and 20 different ligands. Statistical analyses showed that the novel ensemble, which is represented by only 0.48% of the MD conformations, was able to reproduce 75% of all dynamic behaviors within the binding cavity for the docking experiments performed. Moreover, this new approach not only outperforms the other two RMSD-clustering solutions, but it also shows to be a promising strategy to distill biologically relevant information from MD trajectories, especially for docking purposes.</p></div

Statistical evaluations for the optimal partitioning solutions obtained from the best partitions (lowest SQD value) of every clustering method.

<p>Third column indicates the number of medoids used in the statistical assessments. Average, standard deviation and variance were calculated for each set of medoids based on predicted FEB values. Last row indicates the statistical values for the MD’s full trajectory.</p