In
the age of failing small-molecule antibiotics, tapping the near-infinite
structural and chemical repertoire of antimicrobial peptides (AMPs)
offers one of the most promising routes toward developing next-generation
antibacterial compounds. One of the key impediments en route is the
lack of methodologies for systematic rational design and optimization
of new AMPs. Here we present a new simulation-guided rational design
approach and apply it to develop a potent new AMP. We show that unbiased
atomic detail molecular dynamics (MD) simulations are able to predict
structures formed by evolving peptide designs enabling structure-based
rational fine-tuning of functional properties. Starting from a 14-residue
poly leucine template we demonstrate the design of a minimalistic
potent new AMP. Consisting of only four types of amino acids (LDKA),
this peptide forms large pores in microbial membranes at very low
peptide-to-lipid ratios (1:1000) and exhibits low micromolar activity
against common Gram-positive and Gram-negative pathogenic bacteria.
Remarkably, the four amino acids were sufficient to encode preferential
poration of bacterial membranes with negligible damage to red blood
cells at bactericidal concentrations. As the sequence is too short
to span cellular membranes, pores are formed by stacking of channels
in each bilayer leaflet.
Drug development for the treatment of central nervous system (CNS) diseases is extremely challenging, in large part due to the difficulty in crossing the blood-brain barrier (BBB). Here we develop and experimentally validate a new
in silico
method to predict quantitatively the BBB permeability for small-molecule drugs. We show accurate prediction of solute permeabilities at physiological temperature using high-temperature unbiased atomic detail molecular dynamics simulations of spontaneous drug diffusion across BBB bilayers. These simulations provide atomic detail insights into the transport mechanisms, as well as converged kinetics and thermodynamics. The method is validated computationally against physiological temperature simulations for fast-diffusing compounds, as well as experimentally by direct determination of the compound permeabilities using a transwell assay as an
in vitro
BBB model. The overall agreement of the predicted values with both direct simulations at physiological temperatures and experimental data is excellent. This new tool has the potential to replace current semi-empirical
in silico
screening and
in vitro
permeability measurements in CNS drug discovery.
Voltage-gated sodium channels are transmembrane proteins involved in generating action potentials for nerve signalling and muscle contractions. They are of a great deal of interest, as mutations in voltage-gated sodium channels are responsible for a variety of disorders, including epilepsy and chronic pain. Designing better inhibitors and treatments, including ones which are
Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.
The retina has a complex structure with a diverse collection of component cells that work together to facilitate vision. The retinal capillaries supplying the nutritional requirements to the inner retina have an intricate system of neural, glial and vascular elements that interconnect to form the neurovascular unit (NVU). The retina has no autonomic nervous system and so relies on the NVU as an interdependent, physical
Microvascular networks can be modelled as a network of connected cylinders. Presently, however, there are limited approaches with which to recover these networks from biomedical images. We have therefore developed and implemented computer algorithms to geometrically reconstruct three-dimensional (3D) retinal microvascular networks from micrometre-scale imagery, resulting in a concise representation of two endpoints and radius for each cylinder detected within a delimited text file. This format is suitable for a variety of purposes, including efficient simulations of molecular delivery. Here, we detail a semi-automated pipeline consisting of the detection of retinal microvascular volumes within 3D imaging datasets, the enhancement and analysis of these volumes for reconstruction, and the geometric construction algorithm itself, which converts voxel data into representative 3D cylindrical objects.
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