Computational redesign of bacterial biotin carboxylase inhibitors using structure-based virtual screening of combinatorial libraries

As the spread of antibiotic resistant bacteria steadily increases, there is an urgent need for new antibacterial agents. Because fatty acid synthesis is only used for membrane biogenesis in bacteria, the enzymes in this pathway are attractive targets for antibacterial agent development. Acetyl-CoA carboxylase catalyzes the committed and regulated step in fatty acid synthesis. In bacteria, the enzyme is composed of three distinct protein components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. Fragment-based screening revealed that amino-oxazole inhibits biotin carboxylase activity and also exhibits antibacterial activity against Gram-negative organisms. In this report, we redesigned previously identified lead inhibitors to expand the spectrum of bacteria sensitive to the amino-oxazole derivatives by including Gram-positive species. Using 9,411 small organic building blocks, we constructed a diverse combinatorial library of 1.2 × 108 amino-oxazole derivatives. A subset of 9 × 106 of these compounds were subjected to structure-based virtual screening against seven biotin carboxylase isoforms using similarity-based docking by eSimDock. Potentially broad-spectrum antibiotic candidates were selected based on the consensus ranking by several scoring functions including nonlinear statistical models implemented in eSimDock and traditional molecular mechanics force fields. The analysis of binding poses of the top-ranked compounds docked to biotin carboxylase isoforms suggests that: (1) binding of the amino-oxazole anchor is stabilized by a network of hydrogen bonds to residues 201, 202 and 204; (2) halogenated aromatic moieties attached to the amino-oxazole scaffold enhance interactions with a hydrophobic pocket formed by residues 157, 169, 171 and 203; and (3) larger substituents reach deeper into the binding pocket to form additional hydrogen bonds with the side chains of residues 209 and 233. These structural insights into drug-biotin carboxylase interactions will be tested experimentally in in vitro and in vivo systems to increase the potency of aminooxazole inhibitors towards both Gram-negative as well as Gram-positive species. ©2014 by the authors; licensee MDPI, Basel, Switzerland

ESIM_DSN Web-Enabled Distributed Simulation Network

In this paper, the eSim(sup DSN) approach to achieve distributed simulation capability using the Internet is presented. With this approach a complete simulation can be assembled from component subsystems that run on different computers. The subsystems interact with each other via the Internet The distributed simulation uses a hub-and-spoke type network topology. It provides the ability to dynamically link simulation subsystem models to different computers as well as the ability to assign a particular model to each computer. A proof-of-concept demonstrator is also presented. The eSim(sup DSN) demonstrator can be accessed at http://www.jsc.draper.com/esim which hosts various examples of Web enabled simulations

The Enzymes of Biotin Dependent CO(2) Metabolism: What Structures Reveal about Their Reaction Mechanisms

Biotin is the major cofactor involved in carbon dioxide metabolism. Indeed, biotin-dependent enzymes are ubiquitous in nature and are involved in a myriad of metabolic processes including fatty acid synthesis and gluconeogenesis. The cofactor, itself, is composed of a ureido ring, a tetrahydrothiophene ring, and a valeric acid side chain. It is the ureido ring that functions as the CO2 carrier. A complete understanding of biotin-dependent enzymes is critically important for translational research in light of the fact that some of these enzymes serve as targets for anti-obesity agents, antibiotics, and herbicides. Prior to 1990, however, there was a dearth of information regarding the molecular architectures of biotin-dependent enzymes. In recent years there has been an explosion in the number of three-dimensional structures reported for these proteins. Here we review our current understanding of the structures and functions of biotin-dependent enzymes. In addition, we provide a critical analysis of what these structures have and have not revealed about biotin-dependent catalysis

Functional Morphology of Gliding Flight I. Modeling Reveals Distinct Performance Landscapes Based on Soaring Strategies

The physics of flight influences the morphology of bird wings through natural selection on flight performance. The connection between wing morphology and performance is unclear due to the complex relationships between various parameters of flight. In order to better understand this connection, we present a holistic analysis of gliding flight that preserves complex relationships between parameters. We use a computational model of gliding flight, along with analysis by uncertainty quantification, to 1) create performance landscapes of gliding based on output metrics (maximum lift-to-drag ratio, minimum gliding angle, minimum sinking speed, lift coefficient at minimum sinking speed); and 2) predict what parameters of flight (chordwise camber, wing aspect ratio, Reynolds number) would differ between gliding and non-gliding species of birds. We also examine performance based on soaring strategy for possible differences in morphology within gliding birds. Gliding birds likely have greater aspect ratios than non-gliding birds, due the high sensitivity of aspect ratio on most metrics of gliding performance. Furthermore, gliding birds can use two distinct soaring strategies based on performance landscapes. First, maximizing distance traveled (maximizing lift-to-drag ratio and minimizing gliding angle) should result in wings with high aspect ratios and middling-to-low wing chordwise camber. Second, maximizing lift extracted from updrafts should result in wings with middling aspect ratios and high wing chordwise camber. Following studies can test these hypotheses using morphological measurements

Functional Morphology of Gliding Flight II. Morphology Follows Predictions of Gliding Performance

The evolution of wing morphology among birds, and its functional consequences, remains an open question, despite much attention. This is in part because the connection between form and function is difficult to test directly. To address this deficit, in prior work we used computational modeling and sensitivity analysis to interrogate the impact of altering wing aspect ratio, camber, and Reynolds number on aerodynamic performance, revealing the performance landscapes that avian evolution has explored. In the present work, we used a dataset of three-dimensionally scanned bird wings coupled with the performance landscapes to test two hypotheses regarding the evolutionary diversification of wing morphology associated with gliding flight behavior: 1) gliding birds would exhibit higher wing aspect ratio and greater chordwise camber than their non-gliding counterparts; and 2) that two strategies for gliding flight exist, with divergent morphological conformations. In support of our first hypothesis, we found evidence of morphological divergence in both wing aspect ratio and camber between gliders and non-gliders, suggesting that wing morphology of birds that utilize gliding flight is under different selective pressures than the wings of non-gliding taxa. Furthermore, we found that these morphological differences also yielded differences in coefficient of lift measured both at the maximum lift to drag ratio and at minimum sinking speed, with gliding taxa exhibiting higher coefficient of lift in both cases. Minimum sinking speed was also lower in gliders than non-gliders. However, contrary to our hypothesis, we found that the maximum ratio of the coefficient of lift to the coefficient of drag differed between gliders and non-gliders. This may point to the need for gliders to maintain high lift capability for takeoff and landing independent of gliding performance, or could be due to the divergence in flight styles among gliders, as not all gliders are predicted to optimize either quantity. However, direct evidence for the existence of two morphologically defined gliding flight strategies was equivocal, with only slightly stronger support for an evolutionary model positing separate morphological optima for these strategies than an alternative model positing a single peak. The absence of a clear result may be an artifact of low statistical power owing to a relatively small sample size of gliding flyers expected to follow the “aerial search” strategy

Health literacy: impact on the health of HIV-infected individuals.

Health literacy is known to affect vulnerable communities such as persons living with HIV/AIDS. The purpose of this review was to provide a current summary of research on the impact of health literacy on the health of persons living with HIV/AIDS and to address future areas of need. Contemporary studies focused on expanding the reach of health literacy in HIV/AIDS to retention in HIV care, use of technology for assessing and intervening to improve health literacy, and health literacy across the globe, for example. A number of studies did not find health literacy to explain health behaviors whereas other studies supported such a relationship. Future issues relevant to health literacy in HIV/AIDS include the aging of the HIV population and associated comorbidities, studies to understand the role of health literacy in specific populations affected by HIV/AIDS, and the continued need to refine the definition and measurement of health literacy

Baseline medication adherence and response to an electronically delivered health literacy intervention targeting adherence.

Medication adherence in persons treated for human immunodeficiency virus (HIV) continues to be an important focus for intervention. While high levels of adherence are required for good clinical outcomes, research shows many patients do not achieve these levels. Despite multiple interventions to improve adherence, most require multiple sessions delivered by trained clinicians. Cost and lack of trained personnel limit the availability of these interventions. Alternatives to clinician-delivered interventions are interventions provided via electronic devices (eg, personal/tablet computers and smartphones). Modern technology allows devices to provide tailoring of content to patient characteristics and learning needs, and to be excellent platforms to deliver multimedia teaching content. The intervention reported drew on research on health literacy in persons with HIV and the relation of health literacy to medication adherence in persons treated for HIV to develop an electronically delivered application. Using the Information-Motivation-Behavioral Skills model as a conceptual framework for understanding patients\u27 information needs, a computer-delivered intervention was developed, its usability and acceptability was assessed, and medication adherence in 118 patients for 1 month before and after they completed the intervention was evaluated. Changes in participant adherence were evaluated in sequential models with progressively lower levels of baseline medication adherence. Results show that although changes in adherence in the entire sample only approached statistical significance, individuals with adherence less than 95% showed significant increases in adherence over time. Participants\u27 self-reported knowledge and behavioral skills increased over the course of the study. Their change in information predicted their post-intervention adherence, suggesting a link between the intervention\u27s effects and outcomes. A computer-delivered intervention targeting HIV-related health literacy may thus be a useful strategy for improving patient adherence