Conformational landscape and low lying excited states of imatinib

Abstract The conformational changes of imatinib (IMT) are crucial for understanding the ligand–receptor interaction and its mechanism of action [Agofonov et al. (2014) Nature Struct Mol Biol 21:848–853]. Therefore, here we investigated the free energy conformational landscape of the free IMT base, aiming to describe the three-dimensional structures and energetic stability of its conformers. Forty-five unique conformers, within an energy window of 4.8 kcal mol−1 were identified by a conformational search in gas-phase, at the B3LYP/6-31G(d) theoretical level. Among these, the 20most stable, as well as 4 conformers resulting from optimization of experimental structures found in the two known polymorphs of IMTand in the c- Abl complex were further refined using the 6-31+G(d,p) basis set and the polarizable continuum solvation model. The most stable conformers in gas-phase and water exhibit a V-shaped structure. The major difference between the most stable free conformers and the bioactive conformers consists in the relative orientation of the pyrimidine–pyridine groups responsible for hydrogen bonding interactions in the ATP-binding pocket. The ratio of mole fractions corresponding to the two known (α and β) polymorphic forms of IMT was estimated from the calculated thermochemical data, in quantitative agreement with the existing experimental data related to their solubility. The electronic absorption spectrum of this compound was investigated in water and explained based on the theoretical TD-DFT results, considering the Boltzmann populationaveraged computed data at CAM-B3LYP/6-31+G(d,p) level of theory for the nine most stable conformers

Controlling Plasmonic Chemistry Pathways through Specific Ion Effects

Plasmon-driven dehalogenation of brominated purines has been recently explored as a model system to understand fundamental aspects of plasmon-assisted chemical reactions. Here, it is shown that divalent Ca2+ ions strongly bridge the adsorption of bromoadenine (Br-Ade) to Ag surfaces. Such ion-mediated binding increases the molecule's adsorption energy leading to an overlap of the metal energy states and the molecular states, enabling the chemical interface damping (CID) of the plasmon modes of the Ag nanostructures (i.e., direct electron transfer from the metal to Br-Ade). Consequently, the conversion of Br-Ade to adenine almost doubles following the addition of Ca2+. These experimental results, supported by theoretical calculations of the local density of states of the Ag/Br-Ade complex, indicate a change of the charge transfer pathway driving the dehalogenation reaction, from Landau damping (in the lack of Ca2+ ions) to CID (after the addition of Ca2+). The results show that the surface dynamics of chemical species (including water molecules) play an essential role in charge transfer at plasmonic interfaces and cannot be ignored. It is envisioned that these results will help in designing more efficient nanoreactors, harnessing the full potential of plasmon-assisted chemistry

Synthesis, characterization, and in vitro-in ovo toxicological screening of silibinin fatty acids conjugates as prodrugs with potential biomedical applications

Silibinin (SIL), the most active phytocompound from Silybum marianum (L.), exerts many biological effects but has low stability and bioavailability. To overcome these drawbacks, the current research proposed the synthesis of silibilin oleate (SIL-O) and silibilin linoleate (SIL-L) derivatives as prodrugs with potentially optimized properties for biomedical applications, and the establishment of their in vitro-in ovo safety profiles. The physicochemical characterization of the obtained compounds using density functional theory (DFT) calculations, and Raman and 1H liquid-state nuclear magnetic resonance (NMR) spectroscopy confirmed the formation of SIL-O and SIL-L complexes. Computational predictions revealed that these lipophilic derivatives present a lower drug-likeness score (-29.96 for SIL-O and -23.55 for SIL-L) compared to SIL, but an overall positive drug score (0.07) and no risk for severe adverse effects. SIL-O and SIL-L showed no cytotoxicity or impairment in cell migration at low concentrations, but at the highest concentration (100 µM), they displayed distinct toxicological profiles. SIL-L was more cytotoxic (on cardiomyoblasts - H9c2(2-1), hepatocytes - HepaRG, and keratinocytes - HaCaT) than SIL-O or SIL, significantly inhibiting cell viability (< 60%), altering cellular morphology, reducing cell confluence (< 70%), and inducing prominent apoptotic-like nuclear features. At the concentration of 100 µM, SIL-O presented an irritation score (IS) of 0.61, indicating a lack of irritant effect on the chorioallantoic membrane (CAM), while SIL-L was classified as a slight irritant with an IS of 1.99. These findings outline a more favorable in vitro and in ovo biocompatibility for SIL-O compared to SIL-L, whose applications are dosage-limited due to potential toxicity

Towards object-aware development tools

Reasoning about object-oriented applications requires developers to answer contextual questions about their domain objects. Tailored development tools can support developers in this activity by providing relevant domain-specific information. Nonetheless, a high effort for extending development tools to handle domain-specific objects, together with diverging mechanisms for creating, sharing and discovering extensions, discourage developers to adapt their tools. To address this, we propose to enable contextual behavior in development tools by allowing domain objects to decide how they are handled in development tools. We show that combining this idea with mechanisms for specifying extensions using internal DSLs can significantly reduce the cost of tailoring development tools to specific domains

Moldable tools

Development tools are a prerequisite for crafting software. They offer the lenses through which developers perceive and reason about their software systems. Generic development tools, while having a wide range of applicability, ignore the contextual nature of software systems and do not allow developers to directly reason in terms of domain abstractions. Domain-specific development tools, tailored to particular application domains, can address this problem. While it has clear advantages, incorporating domain abstractions into development tools is a challenging activity. The wide range of domains and contextual tasks that development tools need to support leads to costly or ad hoc mechanisms to incorporate and discover domain abstractions. Inherently, this limits developers from taking advantage of domain-specific information during the development and maintenance of their systems. To overcome this problem, we propose to embed domain abstractions into development tools through the design of moldable tools that support the inexpensive creation of domain-specific extensions capturing domain abstractions, and that automatically select extensions based on the domain model and the developer’s interaction with the domain model. This solution aims to reduce the cost of creating extensions. Towards this goal, it provides precise extension points together with internal DSLs for configuring common types of extensions. This solution facilitates automatic discovery by enabling extension creators to specify together with an extension an activation predicate that captures the context in which that extension is applicable. We validate the moldable tools approach by applying it, in the context of objectoriented applications, to improve three development activities, namely: reasoning about run-time objects, searching for domain-specific artifacts, and reasoning about run-time behavior. For each activity we identify limitations of current tools, show how redesigning those tools following the moldable tools approach addresses the identified limitations, and discuss the cost for creating domain-specific extensions. We demonstrate that moldable tools address an existing need by analyzing the increase in domain-specific extensions after we integrated the moldable tools solving the aforementioned tasks with an IDE. We also show what kinds of custom environments developers can create by continuously adapting their development tools

Towards moldable development tools

Developers commonly ask detailed and domain-specific questions about the software systems they are developing and maintaining. Integrated development environments (IDEs) form an essential category of tools for developing software that should support software engineering decision making. Unfortunately, rigid and generic IDEs that focus on low-level programming tasks, that promote code rather than data, and that suppress customization, offer limited support for informed decision making during software development. We propose to improve decision making within IDEs by moving from generic to context-aware IDEs through moldable tools. In this paper, we promote the idea of moldable tools, illustrate it with concrete examples, and discuss future research directions

Pervasive Software Visualizations

A picture tells a thousand words. We all know that. Then why are our development tools showing mainly text with so much obstinacy? Even when visualizations do make it into our tools, they typically do not make it past the periphery. Something is deeply wrong. We argue that visualizations must become pervasive in software development, and to accommodate this goal, the integrated development environments must change significantly

Integrated Management Solution for a Sustainable SME—Selection Proposal Using AHP

In the conditions of the pandemic crisis, implementing an enterprise resource planning (ERP) system with a sustainability component represents a crucial investment for a small and medium enterprise (SME) but critical for the organization, if it is not the matching solution. A comprehensive framework for selecting the S–ERP system was elaborated, including a set of relevant criteria for an SME to draw and assess the selection of an ERP system, considering that the factors extracted as well as the importance in the proposed model have been debated for years in the available literature. A methodology based on the brainstorming and questionnaire techniques was proposed in establishing the selection criteria, and the AHP decision analysis method was used for evaluating the weight of the criteria, all these in order to provide a model for ERP selection. This model was tested on a set of numerical, hypothetical, and applied data of the Romanian context. The use of the recommended model shows that it can be applied to improve decisions and decrease the time interval required for S–ERP selection. The results also show that AHP can fulfill the S–ERP selection objective for SMEs and the decisive factors that affect decision–making processes in a systematic way

A promising approach for debugging remote promises

Promises are synchronization constructs that hide the complexity of process synchronisation from the developer by providing a placeholder for the result of a potentially incomplete computation performed in a concurrent process. Promises evaluated by remote processes pose challenges for debugging when the remote computation raises an exception. Current debuggers are either unaware that there is a problem in the remote computation or give developers access only to the context of the remote process. This does not allow developers to interact at the same time with the process that launched the promise and the remote process that executed the promise's computation. To improve debugging of remote promises, in this paper we propose a debugger interface that presents a unified view of both the original and the remote process, by merging the call chains of the two processes at the point where the promise was created. We exemplify our approach, discuss challenges for making it practical, and illustrate through an initial prototype that it can improve debugging of exceptions in remote promises

PEAR VARIETIES AND SELECTIONS, WITH EXTRA-EARLY AND EARLY RIPENING, OBTAINED AT THE FRUIT RESEARCH STATION CLUJ (FRS CLUJ)

Pear-breeding in the Fruit Research Station Cluj started in 1953 when the Fruit Research Station was founded, carrying the following objectives: productivity, quality and different ripening periods in order to assure fresh fruits for a longer period of time. Due to this activity, the following pear varieties have been certificated: Napoca, Doina, Haydeea, Ina Estival, Virgiliu Hibernal, Jubileu 50 and Milenium. To obtain the first generation of hybrids were used the 400 existent varieties at FRS Cluj. The method used concerning the issue of variety was conducted hybridisation. Taken by the improvement objectives which were proposed, there were chosen as genitors the varieties and selections that were suitable for the aim to follow. At the time being, in the trial fields of FRS Cluj, there are over 140 selections of pear hybrids, obtained by selections. From the large number of tested selections can be noticed a few selections with extra-early and early ripening, with great perspectives for being certificated: 72-17-11, 72-2-16, 72-15-45, 99-7-51, 72-21-13. We recommend studying them in production conditions and promoting the best selections for propagation and for being included in the local and national range of varieties