Перспективи інформаційної економіки

Метою доповіді є дослідження впливу інформаційних технологій на розвиток таких категорій сучасності як перехід сучасної економіки до інформаційного етапу, а також становлення інформаційного суспільства на основі сучасного пост промислового суспільства споживання

The importance of hydraulic groundwater theory in catchment hydrology: The legacy of Wilfried Brutsaert and Jean-Yves Parlange

Based on a literature overview, this paper summarizes the impact and legacy of the contributions of Wilfried Brutsaert and Jean-Yves Parlange (Cornell University) with respect to the current state-of-the-art understanding in hydraulic groundwater theory. Forming the basis of many applications in catchment hydrology, ranging from drought flow analysis to surface water-groundwater interactions, hydraulic groundwater theory simplifies the description of water flow in unconfined riparian and perched aquifers through assumptions attributed to Dupuit and Forchheimer. Boussinesq (1877) derived a general equation to study flow dynamics of unconfined aquifers in uniformly sloping hillslopes, resulting in a remarkably accurate and applicable family of results, though often challenging to solve due to its nonlinear form. Under certain conditions, the Boussinesq equation can be solved analytically allowing compact representation of soil and geomorphological controls on unconfined aquifer storage and release dynamics. The Boussinesq equation has been extended to account for flow divergence/convergence as well as for nonuniform bedrock slope (concave/convex). The extended Boussinesq equation has been favorably compared to numerical solutions of the three-dimensional Richards equation, confirming its validity under certain geometric conditions. Analytical solutions of the linearized original and extended Boussinesq equations led to the formulation of similarity indices for baseflow recession analysis, including scaling rules, to predict the moments of baseflow response. Validation of theoretical recession parameters on real-world streamflow data is complicated due to limited measurement accuracy, changing boundary conditions, and the strong coupling between the saturated aquifer with the overlying unsaturated zone. However, recent advances are shown to have mitigated several of these issues. The extended Boussinesq equation has been successfully applied to represent baseflow dynamics in catchment-scale hydrological models, and it is currently considered to represent lateral redistribution of groundwater in land surface schemes applied in global circulation models. From the review, it is clear that Wilfried Brutsaert and Jean-Yves Parlange stimulated a body of research that has led to several fundamental discoveries and practical applications with important contributions in hydrological modeling.Keywords: Parlange, hillslope, catchment, groundwater, Brutsaert, Boussines

Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery

Significant progress has been made in prospectively designing molecules using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the analysis reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochemical properties. The CNS MPO tool has helped to increase the percentage of compounds nominated for clinical development that exhibit alignment of ADME attributes, cross the blood–brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the number of compounds submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicology into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compounds nominated for clinical development

Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery

Significant progress has been made in prospectively designing molecules using the central nervous system multiparameter optimization (CNS MPO) desirability tool, as evidenced by the analysis reported herein of a second wave of drug candidates that originated after the development and implementation of this tool. This simple-to-use design algorithm has expanded design space for CNS candidates and has further demonstrated the advantages of utilizing a flexible, multiparameter approach in drug discovery rather than individual parameters and hard cutoffs of physicochemical properties. The CNS MPO tool has helped to increase the percentage of compounds nominated for clinical development that exhibit alignment of ADME attributes, cross the blood–brain barrier, and reside in lower-risk safety space (low ClogP and high TPSA). The use of this tool has played a role in reducing the number of compounds submitted to exploratory toxicity studies and increasing the survival of our drug candidates through regulatory toxicology into First in Human studies. Overall, the CNS MPO algorithm has helped to improve the prioritization of design ideas and the quality of the compounds nominated for clinical development

Quantitative Assessment of the Impact of Fluorine Substitution on P‑Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability

Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and p<i>K</i>_a. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MW_FC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor

Chemoproteomics Demonstrates Target Engagement and Exquisite Selectivity of the Clinical Phosphodiesterase 10A Inhibitor MP-10 in Its Native Environment

Phosphodiesterases (PDEs) regulate the levels of the second messengers cAMP and cGMP and are important drug targets. PDE10A is highly enriched in medium spiny neurons of the striatum and is an attractive drug target for the treatment of basal ganglia diseases like schizophrenia, Parkinson’s disease, or Huntington’s disease. Here we describe the design, synthesis, and application of a variety of chemical biology probes, based on the first clinically tested PDE10A inhibitor MP-10, which were used to characterize the chemoproteomic profile of the clinical candidate in its native environment. A clickable photoaffinity probe was used to measure target engagement of MP-10 and revealed differences between whole cell and membrane preparations. Moreover, our results illustrate the importance of the linker design in the creation of functional probes. Biotinylated affinity probes allowed identification of drug-interaction partners in rodent and human tissue and quantitative mass spectrometry analysis revealed highly specific binding of MP-10 to PDE10A with virtually no off-target binding. The profiling of PDE10A chemical biology probes described herein illustrates a strategy by which high affinity inhibitors can be converted into probes for determining selectivity and target engagement of drug candidates in complex biological matrices from native sources

Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy† †Electronic supplementary information (ESI) available. CCDC 1452774. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6md00406g

γ-Secretase modulators for the treatment of Alzheimer's disease. Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4 . The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-β42 (Aβ42) when dosed orally at 10 mg kg –1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds