AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Análisis comparativo del PENX 2003 - 2013 y 2025: Perú, en la búsqueda de la sostenibilidad y competitividad como país exportador

El presente trabajo de investigación tiene como finalidad determinar la existencia de ciertos vacíos dentro de los lineamientos desarrollados en el Plan Estratégico Nacional Exportador 2025 (PENX 2025); es decir, aquellas medidas que fueron planteadas en el PENX 2003 - 2013 pero no en el actual PENX; a partir de un análisis comparativo de ambos planes estratégicos, y de la identificación del grado de impacto de estos con la visión del país dentro del contexto internacional actual. El trabajo de investigación consta de seis capítulos. En el primer capítulo, se muestra un diagnóstico general del comercio internacional y la apertura comercial del Perú entre los años 2003 al 2015, así como también un panorama informativo de ambos planes estratégicos. En el segundo capítulo, se desarrollan los aspectos generales del plan de investigación. Asimismo, en el tercer capítulo, se describe la metodología utilizada a lo largo del trabajo de investigación. Acercándonos a la problemática del trabajo, en el capítulo cuatro se mostrará los logros y/o resultados obtenidos al culminar el horizonte de 10 años que comprende el PENX 2003-2013. En el quinto capítulo se presentan los vacíos encontrados como resultado de un análisis comparativo entre ambos PENX y la evaluación de las tendencias globales, y el impacto que estas generan en el desempeño y la competitividad del país dentro del mercado internacional. Finalmente, en el sexto capítulo, se detallan las conclusiones y recomendaciones obtenidas del análisis a desarrollar.The main objective of the following research is to determine the existence of certain gaps within the guidelines developed in the National Strategic Exporter Plan 2025 (PENX 2025); that is to say, those measures that were outlined in PENX 2003 - 2013 but not in the actual plan; based on a comparative analysis of both strategic plans, and the identification of the degree of impact of these with the vision of the country within the actual international context. This research has six chapters. The first shows a general diagnosis of international trade and open trade in Peru from 2003 to 2015, as well as an informative outlook of both plans. The second chapter develops the general aspects of the research plan. In addition, the third chapter describes the methodology used throughout the research. Approaching the problem of research, in the chapter four will be showed the achievements and results obtained at the end of the 10-year horizon that contains the PENX 2003-2013. In the fifth chapter presents the gaps found as a result of a comparative analysis between both PENX and the evaluation of global trends, and the impact that they generate on the performance and competitiveness of the country within the international market. Finally, in the sixth chapter, defines the conclusions and recommendations about the present analysis.Tesi

Biallelic mutations in the ferredoxin reductase gene cause novel mitochondriopathy with optic atrophy.

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans. Hum Mol Genet 2017 Dec 15; 26(24):4937-4950