Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents.

The emergence of drug-resistant tuberculosis has created an urgent need for new anti-tubercular agents. Here, we report the discovery of a series of macrolides called sequanamycins with outstanding in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb). Sequanamycins are bacterial ribosome inhibitors that interact with the ribosome in a similar manner to classic macrolides like erythromycin and clarithromycin, but with binding characteristics that allow them to overcome the inherent macrolide resistance of Mtb.

The potential impact of dengue vaccination with, and without, pre-vaccination screening.

Background: The World Health Organization defined a 'screen and vaccinate' strategy as its recommended policy for the licensed dengue vaccine (Dengvaxia, Sanofi Pasteur), so that only individuals with previous dengue infection are vaccinated. The objectives of the present study were to build upon a recently published analysis of the benefits and risks associated with dengue vaccination to evaluate the public health impact and cost-effectiveness of a screen and vaccinate strategy.

Methods: The current analysis was based on a previously reported transmission model and added, for the screening part, three rapid diagnostic tests with identical specificity (99%) but alternative sensitivities (50-70-90%) in the detection of prior dengue infection.

REAL-WORLD EVIDENCE OF DENGUE BURDEN ON HOSPITALS IN MEXICO: INSIGHTS FROM THE AUTOMATED SUBSYSTEM OF HOSPITAL DISCHARGES (SAEH) DATABASE.

Background: The incidence of dengue in Mexico has increased in recent decades. It has been suggested that dengue outbreaks may compromise treatment quality in hospitals.

Objective: The objective of the study was to quantify the burden imposed by dengue on hospital services in Mexico.

Assessment of benefits and risks associated with dengue vaccination at the individual and population levels: a dynamic modeling approach.

Background: A case-cohort study, using a novel assay and data from three dengue vaccine efficacy trials, highlighted differences in vaccination outcomes according to baseline serostatus. Based on these results, we explored, with a model, the benefits and risks associated with vaccination.

Research Design And Methods: Parameters of a previously developed transmission model were estimated with subject-level data from a case-cohort study.

Comorbidities increase in-hospital mortality in dengue patients in Brazil.

Dengue remains an unmet public health burden. We determined risk factors for dengue in-hospital mortality in Brazil. Of 326,380 hospitalised dengue cases in 9-45-year-old individuals, there were 971 deaths.

Cost-effectiveness of dengue vaccination in ten endemic countries.

Following publication of results from two phase-3 clinical trials in 10 countries or territories, endemic countries began licensing the first dengue vaccine in 2015. Using a published mathematical model, we evaluated the cost-effectiveness of dengue vaccination in populations similar to those at the trial sites in those same Latin American and Asian countries. Our main scenarios (30-year horizon, 80% coverage) entailed 3-dose routine vaccinations costing US$20/dose beginning at age 9, potentially supplemented by catch-up programs of 4- or 8-year cohorts.

Potential impact of dengue vaccination: Insights from two large-scale phase III trials with a tetravalent dengue vaccine.

Background: A tetravalent dengue vaccine demonstrated its protective efficacy in two phase III efficacy studies. Results from these studies were used to derive vaccination impact in the five Asian (Indonesia, Malaysia, Philippines, Thailand, Vietnam) and the five Latin American countries (Brazil, Colombia, Honduras, Mexico and Puerto Rico) participating in these trials.

Methods: Vaccination impact was investigated with an age-structured, host-vector, serotype-specific compartmental model.

Estimation of parameters related to vaccine efficacy and dengue transmission from two large phase III studies.

Background: A tetravalent dengue vaccine was shown to be efficacious against symptomatic dengue in two phase III efficacy studies performed in five Asian and five Latin American countries. The objective here was to estimate key parameters of a dengue transmission model using the data collected during these studies.

Methods: Parameter estimation was based on a Sequential Monte Carlo approach and used a cohort version of the transmission model.

CODV-Ig, a universal bispecific tetravalent and multifunctional immunoglobulin format for medical applications.

Bispecific immunoglobulins (Igs) typically contain at least two distinct variable domains (Fv) that bind to two different target proteins. They are conceived to facilitate clinical development of biotherapeutic agents for diseases where improved clinical outcome is obtained or expected by combination therapy compared to treatment by single agents. Almost all existing formats are linear in their concept and differ widely in drug-like and manufacture-related properties.

Large-scale comparison of four binding site detection algorithms.

A large-scale evaluation and comparison of four cavity detection algorithms was carried out. The algorithms SiteFinder, fpocket, PocketFinder, and SiteMap were evaluated on a protein test set containing 5416 protein-ligand complexes and 9900 apo forms, corresponding to a subset of the set used earlier for benchmarking the PocketFinder algorithm. For the holo structures, all four algorithms correctly identified a similar amount of pockets (around 95%).

Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets.

We have designed four generations of a low molecular weight fragment library for use in NMR-based screening against protein targets. The library initially contained 723 fragments which were selected manually from the Available Chemicals Directory. A series of in silico filters and property calculations were developed to automate the selection process, allowing a larger database of 1.

Drug-like annotation and duplicate analysis of a 23-supplier chemical database totalling 2.7 million compounds.

We have implemented five drug-like filters, based on 1D and 2D molecular descriptors, and applied them to characterize the drug-like properties of commercially available chemical compounds. In addition to previously published filters (Lipinski and Veber), we implemented a filter for medicinal chemistry tractability based on lists of chemical features drawn up by a panel of medicinal chemists. A filter based on the modeling of aqueous solubility (>1 microM) was derived in-house, as well as another based on the modeling of Caco-2 passive membrane permeability (>10 nm/s).

2D QSAR consensus prediction for high-throughput virtual screening. An application to COX-2 inhibition modeling and screening of the NCI database.

Using classification (SOM, LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-NN, Linear), this paper details the building of eight 2D-QSAR models from a 266 COX-2 inhibitor training set. The predictive performances of these eight models were subsequently compared using an 88 COX-2 inhibitor test set. Each ligand is described by 52 2D descriptors expressed as van der Waals Surface Areas (P_VSA) and its COX-2 binding IC50.

Preliminary screening of some tropical plants for anti-tyrosinase activity.

In our efforts to find new active tyrosinase inhibitors for skin-whitening or antibrowning preparations, we investigated 67 tropical plants belonging to 38 families, which were evaluated for their anti-tyrosinase activity. The results of our investigation show that extracts of 5 plants, Stryphnodendron barbatimao, Portulaca pilosa, Cariniana brasiliensis, Entada africana and Prosopis africana present interesting in vitro mushroom tyrosinase inhibition (over 90%), similar to a positive control: Morus alba. These 5 plants will be studied in order to isolate and identify phytochemical compounds, involved in this biological activity.

Three-dimensional quantitative structure-activity relationships of cyclo-oxygenase-2 (COX-2) inhibitors: a comparative molecular field analysis.

The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to an extensive series of 305 varied diarylheterocyclic derivatives known as COX-2 selective inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective COX-2 inhibitor, was used to derive the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (229 compounds) and subsequently validated with the corresponding test sets (76 compounds).

3D-QSAR CoMFA study on imidazolinergic I(2) ligands: a significant model through a combined exploration of structural diversity and methodology.

Displaying an unprecedented structural diversity, 119 I(2) ligands, and their pK(i) values, were collected and submitted to a comparative molecular fields analysis (CoMFA) study. They were discerned into three structural subsets (A, B, C), to explore the I(2) 3D-QSARs from finite structural systems (A, B, C) to more complex ones (AB, AC, BC, ABC). In addition, various key steps of the CoMFA methology were explored.