192 research outputs found
Interactivity:the missing link between virtual reality technology and drug discovery pipelines
The potential of virtual reality (VR) to contribute to drug design and
development has been recognised for many years. Hardware and software
developments now mean that this potential is beginning to be realised, and VR
methods are being actively used in this sphere. A recent advance is to use VR
not only to visualise and interact with molecular structures, but also to
interact with molecular dynamics simulations of 'on the fly' (interactive
molecular dynamics in VR, IMD-VR), which is useful not only for flexible
docking but also to examine binding processes and conformational changes.
iMD-VR has been shown to be useful for creating complexes of ligands bound to
target proteins, e.g., recently applied to peptide inhibitors of the SARS-CoV-2
main protease. In this review, we use the term 'interactive VR' to refer to
software where interactivity is an inherent part of the user VR experience
e.g., in making structural modifications or interacting with a physically
rigorous molecular dynamics (MD) simulation, as opposed to simply using VR
controllers to rotate and translate the molecule for enhanced visualisation.
Here, we describe these methods and their application to problems relevant to
drug discovery, highlighting the possibilities that they offer in this arena.
We suggest that the ease of viewing and manipulating molecular structures and
dynamics, and the ability to modify structures on the fly (e.g., adding or
deleting atoms) makes modern interactive VR a valuable tool to add to the
armoury of drug development methods.Comment: 19 pages, 3 figure
Interactive molecular dynamics in virtual reality for accurate flexible protein-ligand docking
Simulating drug binding and unbinding is a challenge, as the rugged energy
landscapes that separate bound and unbound states require extensive sampling
that consumes significant computational resources. Here, we describe the use of
interactive molecular dynamics in virtual reality (iMD-VR) as an accurate
low-cost strategy for flexible protein-ligand docking. We outline an
experimental protocol which enables expert iMD-VR users to guide ligands into
and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease,
and recreate their respective crystallographic protein-ligand binding poses
within 5 - 10 minutes. Following a brief training phase, our studies shown that
iMD-VR novices were able to generate unbinding and rebinding pathways on
similar timescales as iMD-VR experts, with the majority able to recover binding
poses within 2.15 Angstrom RMSD of the crystallographic binding pose. These
results indicate that iMD-VR affords sufficient control for users to carry out
the detailed atomic manipulations required to dock flexible ligands into
dynamic enzyme active sites and recover crystallographic poses, offering an
interesting new approach for simulating drug docking and generating binding
hypotheses.Comment: PLOS ON
Determinants of National Guard Mental Health Service Utilization in VA versus Non‐VA Settings
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134155/1/hesr12446.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134155/2/hesr12446-sup-0001-AppendixSA1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134155/3/hesr12446_am.pd
Active site loop engineering abolishes water capture in hydroxylating sesquiterpene synthases
Terpene synthases (TS) catalyze complex reactions to produce a diverse array of terpene skeletons from linear isoprenyl diphosphates. Patchoulol synthase (PTS) from Pogostemon cablin converts farnesyl diphosphate into patchoulol. Using simulation-guided engineering, we obtained PTS variants that eliminate water capture. Further, we demonstrate that modifying the structurally conserved Hα-1 loop also reduces hydroxylation in PTS, as well as in germacradiene-11-ol synthase (Gd11olS), leading to cyclic neutral intermediates as products, including α-bulnesene (PTS) and isolepidozene (Gd11olS). Hα-1 loop modification could be a general strategy for engineering sesquiterpene synthases to produce complex cyclic hydrocarbons without the need for structure determination or modeling
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A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.
ABSTRACT:
Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings.
Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care.
81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire.
Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems.
Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation.
Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care.
Trial registration: ISRCTN21615909
Large-Scale Variation in Wave Attenuation of Oyster Reef Living Shorelines and the Influence of Inundation Duration
One of the paramount goals of oyster reef living shorelines is to achieve sustained and adaptive coastal protection, which requires meeting ecological (i.e., develop a self-sustaining oyster population) and engineering (i.e., provide coastal defense) targets. In a large-scale comparison along the Atlantic and Gulf coasts of the United States, the efficacy of various designs of oyster reef living shorelines at providing wave attenuation was evaluated accounting for the ecological limitations of oysters with regards to inundation duration. A critical threshold for intertidal oyster reef establishment is 50% inundation duration. Living shorelines that spent less than half of the time (\u3c 50%) inundated were not considered suitable habitat for oysters, however, were effective at wave attenuation (68% reduction in wave height). Reefs that experienced \u3e 50% inundation were considered suitable habitat for oysters, but wave attenuation was similar to controls (no reef; ~5% reduction in wave height). Many of the oyster reef living shoreline approaches therefore failed to optimize the ecological and engineering goals. In both inundation regimes, wave transmission decreased with an increasing freeboard (difference between reef crest elevation and water level), supporting its importance in the wave attenuation capacity of oyster reef living shorelines. However, given that the reef crest elevation (and thus freeboard) should be determined by the inundation duration requirements of oysters, research needs to be re-focused on understanding the implications of other reef parameters (e.g. width) for optimising wave attenuation. A broader understanding of the reef characteristics and seascape contexts that result in effective coastal defense by oyster reefs is needed to inform appropriate design and implementation of oyster-based living shorelines globally
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