Novel Ligand-Based Approach to Screening of Large Databases for Paramphistomicide Lead Generation

In this report, non-stochastic and stochastic 2D atom-based linear indices were used to the discrimination of paramphistomicide compounds from inactive ones. Two linear classification-based QSAR models were obtained. These equations, performed considering both non-stochastic and stochastic TOMOCOMD-CARDD descriptors, classify correctly 88.57% of chemicals in database, for a good Mathew’s correlation coefficient of 0.77. A few anthelmintics compounds and other drugs from the Merck Index, Negwer handbook, and Goodman & Gilman were selected/identified by the models as possible paramphistomicide, one of them was found in the recent literature as possessing this activity. The results demonstrate the usefulness of TOMOCOMD-CARDD method for drug discovery of new lead paramphistomicide compounds.En este informe se emplearon índices lineales estocásticos y no estocásticos en 2D, basados en átomos, para discriminar los compuestos de acción paramfistomicida de los inactivos. Se obtuvieron dos modelos lineales QSAR basados en la clasificación. Estas ecuaciones, llevadas a cabo teniendo en cuenta descriptores TOMOCOMD-CARDD tanto estocásticos como no estocásticos, clasifican correctamente el 88,57% de los elementos químicos de la base de datos, arrojando un buen coeficiente de correlación de Mathews del 0,77. Los modelos seleccionaron/identificaron algunos compuestos antihelmínticos y otros fármacos del índice Merck, del manual Negwer y de Goodman & Gilman como posibles paramfistomicidas, y la literatura reciente incluye a uno de ellos como poseedor de esta actividad. Los resultados demuestran la utilidad del método TOMOCOMD-CARDD para el descubrimiento de fármacos y de nuevos compuestos líderes de acción paramfistomicida.Ciencias Experimentale

Dry selection and wet evaluation for the rational discovery of new anthelmintics

Helminths infections remain a major problem in medical and public health. In this report, atom-based 2D bilinear indices, a TOMOCOMD-CARDD (QuBiLs-MAS module) molecular descriptor family and linear discriminant analysis (LDA) were used to find models that differentiate among anthelmintic and non-anthelmintic compounds. Two classification models obtained by using non-stochastic and stochastic 2D bilinear indices, classified correctly 86.64% and 84.66%, respectively, in the training set. Equation 1(2) correctly classified 141(135) out of 165 [85.45%(81.82%)] compounds in external validation set. Another LDA models were performed in order to get the most likely mechanism of action of anthelmintics. The model shows an accuracy of 86.84% in the training set and 94.44% in the external prediction set. Finally, we carry out an experiment to predict the biological profile of our ‘in-house’ collections of indole, indazole, quinoxaline and cinnoline derivatives (∼200 compounds). Subsequently, we selected a group of nine of the theoretically most active structures. Then, these chemicals were tested in an invitro assay and one good candidate (VA5-5c) as fasciolicide compound (100% of reduction at concentrations of 50 and 10 mg/L) was discovered.Yovani Marrero-Ponce acknowledges the support from USFQ with partial finance of project ID5455Peer Reviewe

Defectos visuales no corregidos y su relación con molestias musculo esqueléticas en cuello y espalda alta

Objective: To determine the prevalence of uncorrected ocular anomalies and its association with cervicalgias in a group of workers in the industrial sector. Methodology: Descriptive, correlational, cross-sectional study of 83 workers in the production area of ​​a lamp factory in Cali, 2011. Surveys of demographic, labor and previous visual defects were carried out. Undetected visual defects were evaluated with Snellen E optotype and direct internal and external examination to detect structural abnormalities. The presence of musculoskeletal pain in the neck and upper back was evaluated with the Nordic questionnaire. Results: The predominant visual defect was presbyopia (43.4%). The most prevalent musculoskeletal symptom was neck pain (44.6%). A significant association was found between having some visual defect and neck pain (P = 0.041). Conclusions: A relationship was found between visual defects and musculoskeletal discomfort in the neck. Periodic visual examinations are recommended to avoid the appearance of musculoskeletal disease.Objetivo: Determinar la prevalencia de anomalías oculares no corregidas y su asociación con cervicalgias en grupo de trabajadores del sector industrial. Metodología: Estudio descriptivo, correlacional, de corte transversal en 83 trabajadores del área de producción de una fábrica de lámparas en Cali, año 2011. Se realizaron encuestas de datos demográficos, laborales y defectos visuales previos. Los defectos visuales no detectados se evaluaron con, optotipo Snellen E y examen directo interno y externo para detección de anomalías estructurales. La presencia de dolor osteomuscular en cuello y espalda alta se evaluó con el cuestionario nórdico. Resultados: El defecto visual predominante fue presbicia (43,4%). El síntoma osteomuscularde mayor prevalencia fue dolor de cuello (44,6%). Se encontró una asociación significativa entre tener algún defecto visual y dolor en cuello (P=0,041). Conclusiones: Se encontró una relación entre los defectos visuales y molestias osteomusculares en cuello. Se recomienda realizar exámenes visuales periódicos para evitar la aparición de enfermedad osteomusculares

Clinical and endoscopic features in patients with hospital-acquired diarrhea associated with Clostridium difficile infection

Introduction and aims: Clostridium difficile infection is the main cause of hospital-acquired diarrhea, and the clinical and endoscopic findings in those patients have been studied very little in Mexico. The aim of the present study was to describe those findings. Materials and methods: A prospective cohort study was conducted that included patients with hospital-acquired diarrhea associated with Clostridium difficile diagnosed through polymerase chain reaction. The hypervirulent NAP027 strain was also determined. The clinical and endoscopic findings in the study patients, as well as the variables associated with severity, were analyzed. Results: Of the 127 patients with hospital-acquired diarrhea, 97 were excluded from the study due to lack of colonoscopy. The remaining 39 study patients had a mean age of 48 years, and their most common signs/symptoms were abdominal pain (49%), mucus in stool (41%), and blood in stool (10%). The most common alterations in the laboratory results were leukocytosis in 49%, fecal leukocytes (61%), and hypoalbuminemia (67%). The main risk factor was antibiotic use in 62%, and ceftriaxone was the most widely used. The hypervirulent strain was present in 54% of the cases. Endoscopic abnormalities were found in 87% of the patients. Thirty-eight percent presented with pseudomembranous colitis, with lesions in the left colon in 53%, and in the right colon in 13%. No association was found between proton-pump inhibitor use and Clostridium difficile-associated diarrhea. There was a significant association between hypoalbuminemia (< 3.3 g/dL) and a greater risk for severe colitis, with a RR of 8.2 (p = 0.008). Conclusions: Pseudomembranous colitis lesions associated with the hypervirulent Clostridium difficile strain were predominant in the left colon. Hypoalbuminemia was a significant severity predictor. Resumen: Introducción y objetivos: La infección por Clostridium difficile (CD) es la causa principal de diarrea en hospitalizados. Los hallazgos clínicos y endoscópicos han sido poco estudiados en nuestro país. El objetivo de este estudio es describir estos hallazgos. Material y métodos: Estudio de cohorte prospectivo, se incluyeron pacientes con diarrea hospitalaria asociada a CD, diagnosticada mediante PCR y determinación de cepa hipervirulenta NAP027. Se analizaron los hallazgos clínicos y endoscópicos, así como las variables asociadas a severidad. Resultados: De 127 pacientes con diarrea hospitalaria, se excluyeron 97 por falta de colonoscopia. De los 39 pacientes incluidos, con edad promedio de 48 años, los signos/síntomas más comunes fueron dolor abdominal (49%), moco en heces (41%) y sangre en heces (10%); las alteraciones de laboratorio más comunes fueron leucocitosis en el 49%, leucocitos en heces (61%) e hipoalbuminemia (67%). El factor de riesgo principal fue el uso de antibiótico en un 62%, más comúnmente la ceftriaxona. La cepa hipervirulenta se presentó en el 54%. Se encontraron anormalidades endoscópicas en el 87%, con colitis seudomembranosa en un 38%, presentándose en colon izquierdo (53%) y en derecho (13%). No se encontró asociación entre uso de IBP y diarrea por CD. Se identificó una asociación significativa entre la hipoalbuminemia (< 3.3 g/dL) y un mayor riesgo de colitis severa, con un RR de 8.2 (p = 0.008). Conclusiones: Las lesiones de colitis seudomembranosa asociada a CD de cepa hipervirulenta predominan en colon izquierdo. La hipoalbuminemia es un predictor significativo de severidad. Keywords: Clostridium difficile, Pseudomembranous colitis, Colonoscopy, NAP027 strain, Palabras clave: Clostridium difficile, Colitis seudomembranosa, Colonoscopia, Cepa NAP02

Discovery of Novel Trichomonacidals Using LDA-Driven QSAR Models and Bond-Based Bilinear Indices as Molecular Descriptors

Few Years ago, the World Health Organization estimated the number of adults with trichomoniasis at 170 million worldwide, more than the combined numbers for gonorrhea, syphilis, and chlamydia. To combat this sexually transmitted disease, Metronidazole (MTZ) has emerged, since 1959, as a powerful drug for the systematic treatment of infected patients. However, increasing resistance to MTZ, adverse effects associated to high-dose MTZ therapies and very expensive conventional technologies related to the development of new trichomonacidals necessitate novel computational methods that shorten the drug discover), pipeline. Therefore, bond-based bilinear indices, new 2-D bond-based TOMOCOMD-CARDD Molecular Descriptors (MDs), and Linear Discriminant Analysis (LDA) are combined to discover novel antitrichomonal agents. Generated models, using non-stochastic and stochastic indices, are able to classify correctly the 90.11% (93.75%) and the 87.92% (87.50%) of chemicals in the training (test) sets, respectively. In addition, they show large Matthews' correlation coefficients (C) of 0.80 (0.86) and 0.76 (0.71) for the training (test) sets, respectively. The result of predictions on the 10% full-out cross-validation test also evidences the quality of both models. In order to test the models' predictive power, 12 compounds, already proved against Trichomonas vaginalis (Tv), are screened in a simulated virtual screening experiment. As a result, they correctly classified 9 out of 12 (75.00%) and 10 out of 12 (83.33%) of the chemicals, respectively, which were the most important criteria to validate the models. Finally, in order to prove the reach of TOMOCOMD-CARDD approach and to discover new trichomonacidals, these classification functions were applied to a set of eight chemicals which, in turn, were synthesized and tested toward in vitro activity against Tv. As a result, experimental observations confirm theoretical predictions to a great extent, since it is gained a correct classification of 87.50% (7/8) of chemicals. Biological tests also show several candidates as antitrichomonals, since almost all the compounds [VAM2-(3-8)] exhibit pronounced cytocidal activities of 100% at the concentration of 100 mu g/mL and at 24 h (48 h) but VAM2-2: 99.37% (100%), and it is remarkable that these compounds do not show toxic activity in macrophage assays at this concentration. The Quantitative Structure-Activity Relationship (QSAR) models presented here could significantly reduce the number of synthesized and tested compounds as well as could act as virtual shortcuts to new chemical entities with trichomonacidal activity