The benefits of in silico modeling to identify possible small-molecule drugs and their off-target interactions

Accepted for publication in a future issue of Future Medicinal Chemistry.The research into the use of small molecules as drugs continues to be a key driver in the development of molecular databases, computer-aided drug design software and collaborative platforms. The evolution of computational approaches is driven by the essential criteria that a drug molecule has to fulfill, from the affinity to targets to minimal side effects while having adequate absorption, distribution, metabolism, and excretion (ADME) properties. A combination of ligand- and structure-based drug development approaches is already used to obtain consensus predictions of small molecule activities and their off-target interactions. Further integration of these methods into easy-to-use workflows informed by systems biology could realize the full potential of available data in the drug discovery and reduce the attrition of drug candidates.Peer reviewe

Elemental fingerprinting of Hypericum perforatum (St John's Wort) herb and preparations using ICP-OES and chemometrics

This is a pre-copyedited, author-produced PDF of an article accepted for publication in Journal of Pharmaceutical and Biomedical Analysis following peer review. The version of record [Journal of Pharmaceutical and Biomedical Analysis (June 2016) Vol 125 pp 15-21, first published online March 4, 2016] is available online at doi: http://dx.doi.org/10.1016/j.jpba.2016.02.054 © 2016 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/St. John's wort (SJW) (Hypericum perforatum) is a herbal remedy commonly used to treat mild depression. The elemental profiles of 54 samples (i.e., dry herbs, tablets and capsules) were evaluated by monitoring 25 elements using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). The major elemental constituents in the SJW samples were Ca (300-199,000 μg/g), Mg (410-3,530 μg/g), Al (4.4-900 μg/g), Fe (1.154-760 μg/g), Mn (2.4-261 μg/g), Sr (0.88-83.6 μg/g), and Zn (7-64 μg/g). For the sixteen elements that could be reliably quantified, principal component analysis (PCA) was used to investigate underlying patterns in the data. PCA models identified 7 key elements (i.e., Ba, Ca, Cd, Mg, Mo, Ni and Y), which described 85% of the variance in the dataset in the first three principal components. The PCA approach resulted in a general delineation between the three different formulations and provides a basis for monitoring product quality in this manner.Peer reviewe

A drug-incorporated-microparticle-eggshell-membrane-scaffold (DIMES) dressing: a novel biomaterial for localised wound regeneration

Chronic wounds affect millions of people annually and have emotional and financial Implications in addition to health issues. The current treatment for chronic wounds involves the repeated use of bandages and drugs such as antibiotics over an extended period. A cost-effective and convenient solution for wound healing is the development of drug-incorporated bandages. This study aimed to develop a biocompatible bandage made of drug-incorporated poly (lactic-co-glycolic acid) (PLGA) microparticles (MPs) and eggshell membrane (ESM) for cornea wound healing. ESM has desirable properties for wound healing and can be isolated from eggshells using acetic acid or ethylenediaminetetraacetic acid (EDTA) protocols. Fluorescein isothiocyanate-labelled Bovine Serum Albumin (FITC-BSA) was used as a model drug, and the PLGA MPs were fabricated using a solvent extraction method. The MPs were successfully attached to the fibrous layer of the ESM using NaOH. The surface features of the ESM samples containing MPs were studied using a field emission scanning electron microscope (FESEM) and compared with blank ESM images. The findings indicated that the MPs were attached to the ESM fibres and had similar shapes and sizes as the control MPs. The fibre diameters of the MPs samples were assessed using Fiji-ImageJ software, and no significant changes were observed compared to the blank ESM. The surface roughness, Ra values, of the MPs incorporated ESM samples were evaluated and compared to the blank ESM, and no significant changes were found. Fourier transform infrared (FTIR) spectroscopy was used to analyse the chemical Composition of the bandage, and the spectra showed that the FBM were effectively incorporated into the ESM. The FTIR spectra identified the major peaks of the natural ESM and the PLGA polymer in the bandage. The bandage was transparent but had a reduced visibility in the waterproof test card method. The bandage achieved sustained drug release up to 10 days and was found to be biocompatible and non-toxic in a chorioallantoic membrane (CAM) assay. Overall, the drug-incorporated PLGA MPs-ESM bandage has great potential for treating chronic wounds

Multivariate analytical approaches to identify key molecular properties of vehicles, permeants and membranes that affect permeation through membranes

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)There has been considerable recent interest in employing computer models to investigate the relationship between the structure of a molecule and its dermal penetration. Molecular permeation across the epidermis has previously been demonstrated to be determined by a number of physicochemical properties, for example, the lipophilicity, molecular weight and hydrogen bonding ability of the permeant. However little attention has been paid to modeling the combined effects of permeant properties in tandem with the properties of vehicles used to deliver those permeants or to whether data obtained using synthetic membranes can be correlated with those obtained using human epidermis. This work uses Principal Components Analysis (PCA) to demonstrate that, for studies of the diffusion of three model permeants (caffeine, methyl paraben and butyl paraben) through synthetic membranes, it is the properties of the oily vehicle in which they are applied that dominated the rates of permeation and flux. Simple robust and predictive descriptor-based quantitative structure–permeability relationship (QSPR) models have been developed to support these findings by utilizing physicochemical descriptors of the oily vehicles to quantify the differences in flux and permeation of the model compounds. Interestingly, PCA showed that, for the flux of co-applied model permeants through human epidermis, the permeation of the model permeants was better described by a balance between the physicochemical properties of the vehicle and the permeant rather than being dominated solely by the vehicle properties as in the case of synthetic model membranes. The important influence of permeant solubility in the vehicle along with the solvent uptake on overall permeant diffusion into the membrane was substantiated. These results confirm that care must be taken in interpreting permeation data when synthetic membranes are employed as surrogates for human epidermis; they also demonstrate the importance of considering not only the permeant properties but also those of both vehicle and membrane when arriving at any conclusions relating to permeation data.Peer reviewedFinal Published versio

The influence of oily vehicle composition and vehicle-membrane interactions on the diffusion of model permeants across barrier membranes

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)In many instances, one or more components of a pharmaceutical or cosmetic formulation is an oil. The aims of this study were two-fold. First, to examine the potential of preferential uptake of one oily vehicle component over another into a model barrier membrane (silicone) from blended vehicles (comprising two from the common excipients isohexadecane (IHD), hexadecane (HD), isopropyl myristate (IPM), oleic acid (OA) and liquid paraffin). Second, to study the effect of membrane-vehicle interactions on the diffusion of model permeants (caffeine (CF), methyl paraben (MP) and butyl paraben (BP)) from blended vehicles. Selective sorption and partition of some oils (especially IHD and IPM) at the expense of other oils (such as OA) was demonstrated to take place. For example, the membrane composition of IHD was enriched compared to a donor solution of IHDOA: 41%, 63% and 82% IHD, compared to donor solution composition of 25%, 50% and 75% IHD, respectively. Pre-soaking the membrane in IHD, HD or LP, rather than phosphate buffer, enhanced the flux of MP through the membrane by 2.6, 1.7 and 1.3 times, respectively. The preferential sorption of individual oil components from mixtures altered the barrier properties of silicone membrane, and enhanced the permeation of CF, MP and BP, which are typically co-formulated in topical products.Peer reviewedFinal Published versio

Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Pharmaceutical Sciences after peer review and technical editing by the publisher. Under embargo. Embargo end date: 9 November 2017. The version of record, Joanna Muddle, Stewart B. Kirton, Irene Parisini, Andrew Muddle, Darragh Murnane, Jogoth Ali, Marc Brown, Clive Page and Ben Forbes, ‘Predicting the Fine Particle Fraction of Dry Powder Inhalers Using Artificial Neural Networks’, Journal of Pharmaceutical Sciences, Vol 106(1): 313-321, first published online on 9 November 2016, is available online via doi: http://dx.doi.org/10.1016/j.xphs.2016.10.002 0022-3549/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.Dry powder inhalers are increasingly popular for delivering drugs to the lungs for the treatment of respiratory diseases, but are complex products with multivariate performance determinants. Heuristic product development guided by in vitro aerosol performance testing is a costly and time-consuming process. This study investigated the feasibility of using artificial neural networks (ANNs) to predict fine particle fraction (FPF) based on formulation device variables. Thirty-one ANN architectures were evaluated for their ability to predict experimentally determined FPF for a self-consistent dataset containing salmeterol xinafoate and salbutamol sulfate dry powder inhalers (237 experimental observations). Principal component analysis was used to identify inputs that significantly affected FPF. Orthogonal arrays (OAs) were used to design ANN architectures, optimized using the Taguchi method. The primary OA ANN r2 values ranged between 0.46 and 0.90 and the secondary OA increased the r2 values (0.53-0.93). The optimum ANN (9-4-1 architecture, average r2 0.92 ± 0.02) included active pharmaceutical ingredient, formulation, and device inputs identified by principal component analysis, which reflected the recognized importance and interdependency of these factors for orally inhaled product performance. The Taguchi method was effective at identifying successful architecture with the potential for development as a useful generic inhaler ANN model, although this would require much larger datasets and more variable inputs.Peer reviewe

Thermoresponsive Triblock‐Copolymers of Polyethylene Oxide and Polymethacrylates: Linking Chemistry, Nanoscale Morphology, and Rheological Properties

© 2021 The Authors. Advanced Functional Materials published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, https://creativecommons.org/licenses/by/4.0/Abstract: Thermoreversible gels switch from a free‐flowing liquid state to an elastic gel mesophase upon warming, displaying the reverse transition upon cooling. While this phenomenon makes these advanced materials highly attractive in numerous fields, the generation of optimal materials of tailored rheology and transition temperatures is stifled by the lack of design principles. To address this need, a library of ABA copolymers has been prepared with “A” blocks exhibiting thermoresponsive behavior and “B” blocks of poly(ethylene glycol). This library evaluates the effect of “A” chemistry, probing three polymer classes, and A/B block molecular weight on thermally‐induced phase changes in solutions of the polymers. An exploration by rheometry coupled to Small‐Angle Neutron Scattering (SANS) elucidates temperature‐dependent hierarchical self‐assembly processes occurring on the nanoscale as well as bulk rheology. This process deciphered links between rheology and supracolloidal assemblies (sphere, ellipses, and cylinders) within the gel state with interactions probed further via structure factors. Several design principles are identified to inform the genesis of next‐generation thermoreversible gels, alongside novel materials exhibited thermoresponsive behavior in the solution state for use in applied healthcare technologies.Peer reviewedFinal Published versio

Small molecule recognition of mephedrone using an anthracene molecular clip

This document is the Accepted Manuscript version of the following article: Kathryn Kellett, J. Hugh Broome, Mire Zloh, Stewart B. Kirton, Suzanne Fergus, Ute Gerhard, Jacqueline Stair, and Kar J. Wallace, ‘Small molecule recognition of mephedrone using an anthracene molecular clip’, Chemical Communications, Vol. 52(47): 7474-7477, 2016. The version of record is available online at DOI: http://dx.doi.org/10.1039/C6CC03404G. Published by the Royal Society of Chemistry.An anthracene molecular probe has been synthesised and shown to target mephedrone, a stimulant drug from the cathinone class of new psychoactive substances (NPS). A protocol has been developed to detect mephedrone via the probe using NMR spectroscopy in a simulated street sample containing two of the most common cutting agents, benzocaine and caffeine.Peer reviewedFinal Accepted Versio

The eggshell membrane : A potential biomaterial for corneal wound healing

The eggshell membrane (ESM) is an abundant resource with innate complex structure and composition provided by nature. With at least 60 million tonnes of hen eggs produced globally per annum, utilisation of this waste resource is highly attractive in positively impacting sustainability worldwide. Given the morphology and mechanical properties of this membrane, it has great potential as a biomaterials for wound dressing. However, to date, no studies have demonstrated nor reported this application. As such, the objective of this investigation was to identify and optimise a reproducible extraction protocol of the ESM and to assess the physical, chemical, mechanical and biological properties of the substrate with a view to use as a wound dressing. ESM samples were isolated by either manual peeling (ESM-strip) or via extraction using acetic acid [ESM-A0.5] or ethylenediaminetetraacetic acid, EDTA [ESM-E0.9]. Energy dispersive X-ray spectroscopy (EDS) confirmed that there were no traces of calcium residues from the extraction process. Fourier transform infrared (FTIR) spectroscopy revealed that the extraction method (acetic acid and EDTA) did not alter the chemical structures of the ESM and also clarified the composition of the fibrous proteins of the ESM. Scanning electron microscopy (SEM) analyses revealed a three-layer composite structure of the ESM: an inner layer as continuous, dense and non-fibrous (limiting membrane), a middle layer with a network of fibres (inner shell membrane) and the outer layer (outer shell membrane) of larger fibres. Material properties including optical transparency, porosity, fluid absorption/uptake, thermal stability, mechanical profiling of the ESM samples were performed and demonstrated suitable profiles for translational applications. Biological in vitro studies using SV40 immortalised corneal epithelial cells (ihCEC) and corneal mesenchymal stromal cells (C-MSC) demonstrated excellent biocompatibility. Taken together, these results document the development of a novel sustainable biomaterial that may be used for ophthalmic wounds and/or other biomedical therapies.Peer reviewe