The Oxindole Derivatives, New Promising GSK-3β Inhibitors as One of the Potential Treatments for Alzheimer’s Disease—A Molecular Dynamics Approach

The glycogen synthase kinase 3β (GSK-3β) is a protein kinase involved in regulating numerous physiological processes such as embryonic development, transcription, insulin action, cell division cycle and multiple neuronal functions. The overexpression of this enzyme is related to many diseases such as schizophrenia, Alzheimer’s disease, diabetes and cancer. One of the basic methods of treatment in these cases is the usage of ATP-competitive inhibitors. A significant group of such compounds are indirubin and its analogs, e.g., oxindole derivatives. The compounds considered in this work are 112 newly designed oxindole derivatives. In the first stage, such molecular properties of considered compounds as toxicity and LogP were estimated. The preliminary analysis of the binding capabilities of considered compounds towards the GSK-3β active site was conducted with the use of the docking procedure. Based on obtained molecular properties and docking simulations, a selected group of complexes that were analyzed in the molecular dynamics stage was nominated. The proposed procedure allowed for the identification of compounds such as Oxind_4_9 and Oxind_13_10, which create stable complexes with GSK-3β enzyme and are characterized by the highest values of binding affinity. The key interactions responsible for stabilization of considered ligand–protein complexes were identified, and their dynamic stability was also determined. Comparative analysis including analyzed compounds and reference molecule 3a, which is also an oxindole derivative with a confirmed inhibitory potential towards GSK3B protein, clearly indicates that the proposed compounds exhibit an analogous binding mechanism, and the obtained binding enthalpy values indicate a slightly higher binding potential than the reference molecule.

Ligand-Based Virtual Screening, Molecular Docking, Molecular Dynamics, and MM-PBSA Calculations towards the Identification of Potential Novel Ricin Inhibitors

Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.

Tuning the optoelectronic properties of Benzo Thiophene (BT-CIC) based non-fullerene acceptor organic solar cell

Organic solar cells have become a center of attention in the field of research and technology due to its remarkable features. In the current research work, we designed Benzo Thiophene (BT-CIC) based non-fullerene acceptor organic solar cell having A-D-A novel structure. The designed structures D1-D4 were derived from BT-CIC (non-fullerene acceptor) by replacing 2-(5,6-dichloro-2-methylene-3-oxo-2,3-dihydro-1H-inden-1-ylidene)acetonitrile of reference molecule R with different electron withdrawing end-capper acceptor moieties. The effect of end acceptor groups on absorption, energy level, charge transport, morphology, and photovoltaic properties of the designed molecules (D1-D4) were investigated by TD-DFT B3LYP/6-31G basic level of theory and compared with reference molecule R. Among all novel structures, D3 exhibited maximum absorption ([Formula: see text]) of 701.7[Formula: see text]nm and 755.2[Formula: see text]nm in gaseous state anfd chloroform, respectively. The red shift in D3 was due to the presence of strong electron withdrawing acceptor moiety and more extended conjugation as compared to other structures. D3 also displayed lowest values of energy bandgap (1.97 eV), [Formula: see text] (0.0063[Formula: see text]eV) and [Formula: see text] (0.0099[Formula: see text]eV) and which signify its ease electron mobility. Lowest value of binding energy 1.20[Formula: see text]eV of D3 suggested that this molecule could be easily dissociated into charge carriers TDM results revealed that easy exciton dissociation occurred in D3. Overall, designed structure D3 was found to be more effective and efficient acceptor molecule for SMOSCs. The findings provide novel information for the development of non-fullerene acceptors for OPVs.

P35 An experience of switching paediatric inflammatory bowel disease patients on infliximab therapy to the biosimilar ‘remsima’

IntroductionThe treatment of inflammatory bowel disease (IBD) with anti-tumour necrosis factor (anti-TNF) biologic therapies such as infliximab is expensive, due to the complex development and manufacturing processes involved with the drug. The number of paediatric patients (PP) receiving infliximab at our trust is increasing, leading to NHS cost pressures. The patent for the infliximab reference molecule Remicade has expired and considerably cheaper biosimilar products are now available, such as Remsima. The license for Remsima was based on adult rheumatology patients; this data was then extrapolated across all licenses. There are currently no long term safety studies of Remsima in children.A biosimilar drug can be defined as ‘a biotherapeutic product that is similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product.’1AimWe wanted to switch all PP receiving infliximab for IBD at our trust from Remicade to a new biosimilar product – Remsima.MethodThe paediatric gastroenterology MDT agreed that all new patients started on infliximab since spring 2016 would be treated with Remsima.Information was gathered regarding the safety, switchability and efficacy of Remsima before the change was made.2 For existing patients, we also contacted other trusts who had already made the switch to gain from their experience. Our current patients on Remsima were reviewed, and no problems were reported.Existing patients were identified and a letter informing their parent/guardian of why we were changing from Remicade to Remsima was posted. An agreed date after which the switch in treatment would occur allowed any concerns or questions to be addressed on previous visits to the hospital.ResultsOverall, the method used was a success: all but one of the identified patients agreed to switch to Remsima – one family refused and the child continues to receive Remicade treatment. All patients on Remsima continue to be monitored closely for adverse reactions or a decline in their disease control. Infliximab levels and antibodies are checked as per local guidelines. Any adverse reactions are reported to the MHRA via the yellow card scheme; Remsima is a black triangle medicine.3ConclusionBiosimilar medicines present a considerable cost saving to the NHS, and by switching our paediatric IBD patients receiving treatment with infliximab from the reference molecule Remicade to the biosimilar Remsima, the Trust has been able to take advantage of this.The saving is substantial and across our 60+patients is somewhere in the region of £250,000 – £2 75 000 a year. This money can be reinvested into the paediatric IBD service to improve patient care. We hope that our experience of switching can be used to support other Trusts in following suit.As further biosimilar medications become available, the NHS could continue to benefit by switching patients receiving biologic treatment.

Unusual co-crystal of isonicotinamide: the structural landscape in crystal engineering

The idea of a structural landscape is based on the fact that a large number of crystal structures can be associated with a particular organic molecule. Taken together, all these structures constitute the landscape. The landscape includes polymorphs, pseudopolymorphs and solvates. Under certain circumstances, it may also include multi-component crystals (or co-crystals) that contain the reference molecule as one of the components. Under still other circumstances, the landscape may include the crystal structures of molecules that are closely related to the reference molecule. The idea of a landscape is to facilitate the understanding of the process of crystallization. It includes all minima that can, in principle, be accessed by the molecule in question as it traverses the path from solution to the crystal. Isonicotinamide is a molecule that is known to form many co-crystals. We report here a 2:1 co-crystal of this amide with 3,5-dinitrobenzoic acid, wherein an unusual N−H⋯N hydrogen-bonded pattern is observed. This crystal structure offers some hints about the recognition processes between molecules that might be implicated during crystallization. Also included is a review of other recent results that illustrate the concept of the structural landscape.